SEARCH RESULTS FOR: Inflammation

systemic-lupus-erythematosus-gastrointestinal-manifestations

Systemic Lupus Erythematosus: Gastrointestinal Manifestations Abbreviations: • APLA Phospholipid — Anti-Antibodies 1— Production of auto-antibodies APLA in circulation promotes blood coagulation —01• Thrombosis of vessels in the pancreas Micro-thrombi of vessels in the liver Liver infarcts Thrombosis of vessels in the small intestine Acute Pancreatitis Death of liver cells release contents into blood stream Thrombus in the hepatic vein • Vascular Damage Mesenteric Vasculitis/Ischemia Budd Chiari Syndrome Damage to Auerbach's Plexus 11` Liver Enzymes 1` in capillary permeability Abnormal release of inflammatory cytokines 1 Inflammation in esophageal muscles Protein-Losing Enteropathy Ascites Note: The gastrointestinal manifestations of systemic lupus erythematosus are due to multifactorial and complex causes, some of which are unknown. Legend: Pathophysiology Mechanism Impaired motor innervation Authors: Joseph Tropiano Reviewers: Zaini Sarwar Harjot Atwal Liam Martin* * MD at time of publication Abnormal production of immune complexes Immune complex deposition in blood vessels Immune complex deposition in smooth muscle Inflammatory reaction in the GI tract Immune complex mediated vasculitis Chronic ischemia of bowel smooth muscle Muscular damage Myopathy or neurogenic pathology of the GI muscles GI muscle damage not severe enough to inhibit peristalsis completely Esophageal Motility Disorders Dysphagia Sign/Symptom/Lab Finding Complications Hypomotility Dysmotility

esophageal-gastric-varices

Esophageal/Gastric Varices: Pathogenesis and clinical findings Schistosomiasis Schistosoma species enter the body through the skin and circulate to liver Eggs lodge in terminal portal venules causing inflammation and fibrosis • 1` resistance through fibrosed and inflamed sinusoids Cirrhosis Liver disease activates hepatic stellate cells causing hepatic fibrosis • I` resistance through fibrosed and distorted sinusoids • 1` portal inflow due to splanchnic vasodilation Veno-Occlusive Disease Budd-Chiari Syndrome Endothelial damage Hypercoagulable in the sinusoids leads to clotting states* cause factor deposition in thrombosis of hepatic sinusoids hepatic veins 1` resistance t resistance through through hepatic occluded distal veins occluded sinusoids by thrombus ► Intra Hepatic Portal Hypertension Post Hepatic Portal Portal Vein Thrombosis Hypercoagulable states* cause thrombosis of portal vein Infiltrative Lesion • Primary or secondary malignancy localized to the portal vein Splenic Vein Thrombosis Pancreatitis leads to inflammation and thrombosis of the splenic vein 1 resistance through '1' resistance through 1` resistance through portal vein occluded portal vein occluded by splenic vein occluded by thrombus malignancy by thrombus Pre Hepatic Portal Hypertension Hypertension *Hypercoagulable states such as thrombophilia, malignancy, or connective tissue disease Portal esophageal/gastric Esophageal/Gastric blood flow backed anastomoses up into Varices As variceal pressure 1` vessels swell 4— Blood loss from circulation 1 vessel J, wall thickness 1 vessel size tension Dilation of veins in submucosa Blood oxidized and vomited or passed through GI Authors: Bigger Varices Variceal rupture Upper GI bleed Gabriel Burke Reviewers: Vadim lablokov Laura Byford-Richardson Meredith Borman* * MD at time of publication • Red Wale Mark or Cherry Red Spot Blood loss too rapid to be oxidized before emesis or passage of GI (visualized on endoscopy) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications • Venous drainage of spleen backed up into gastric anastomoses Tachycardia and hypotension Anemia Death Melena Coffee ground emesis Hematemesis Bright red blood per rectum

central-retinal-artery-occlusion-pathogenesis-and-clinical-findings

Central Retinal Artery Occlusion: Pathogenesis and clinical findings Inflammatory Disease: Cardiogenic Embolism: Hypercoagulable state: Hematologic Disease: (i.e. GCA, SLE, GPA) (i.e. Valvular, arrhythmias, congenital defects) (i.e. OCP, Protein C&S deficiency, ATIII deficiency) (i.e. leukemia/lymphoma, sickle cell, polycythemia) Endothelial cell damage Abnormal blood flow 1` coagulation and/or 1 blood viscosity and creates hypercoagulable state causing localized stasis 4, anti-coagulation inflammation Abbreviations: • GCA — Giant Cell Arteritis • SLE — Systemic Lupus Erythematosus • GPA — granulomatosis with polyangitis • OCP — Oral contraceptive pill • ATIII — Anti-thrombin Ill Thrombus formation Blockage of central retinal artery Central Retinal Artery Occlusion (CRAO) Authors: Graeme Prosperi-Porta Reviewers: Stephanie Cote Usama Malik Johnathan Wong* * MD at time of publication Carotid Artery Atherosclerosis Atherosclerotic plaque dislodges from carotid artery The retina becomes pale 4, perfusion of retinal Slow retinal artery blood Acute retinal edema Ganglion cells and axons from NI, perfusion arterioles due to upstream flow allows for caused by ischemia results death due to ischemia CRAO segmentation of the blood column in a blurred appearance of the retina results in disc pallor seen months after CRAO The choroidal vessels supplying the macula via the posterior ciliary artery become more prominent within a background of retinal pallor

infectious-esophagitis-pathogenesis-and-clinical-findings

Infectious Esophagitis: Pathogenesis and clinical findings HIV/AIDS Radiation therapy Chemotherapy Organ Transplant Antibiotics I/Esophageal motility Tir CD4+ T cells 4,Monocyte and Corticosteroid and granulocyte precursors anti-TNF therapy • • Immunosuppression Note: Bacterial causes of infectious esophagitis are difficult to isolate as they are often polymicrobial in nature and derived from normal oral flora. Cytomegalovirus Infection of endothelial cells and fibroblasts I, Protective flora 4, Pathogen clearance Authors: David Deng Reviewers: Peter Bishay Vadim lablokov Kirles Bishay* MD at time of publication Mechanical stricture Inflammation Ulceration ,..,4 Dysphagia Infectious Viral Bacterial infection infection esophagitis • Fungal infection Odynophagia (i.e. Candida) Herpes Simplex Infection of squamous cells and macrophages Colonization facilitated by use of antacid therapy Nuclear Large Superficial Squamous Macrophage inclusion bodies esophageal ulceration ulcers cell inclusion bodies aggregation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Spores and pseudohyphae seen on biopsy • Invas.on of underlying blood vessels • White plaques over erythematous base '1' neutrophils due to inflammatory response

Primary Spontaneous Pneumothorax: Pathogenesis and clinical findings

Primary Spontaneous Pneumothorax: Pathogenesis and clinical findings Thoracic Tall, thin endometriosis males Genetic Factors (i.e. FLCN mutations, HCY, MFS, CTD) Malnutrition Smoking Structurally compromised lung parenchyma Notes: • PSPs usually occur at rest • Respiratory symptoms vary in severity • Suspect thoracic endometriosis in young women with recurrent PSPs that coincide with menstruation • *Pathophysiology of tension pneumothorax is described in a separate slide Air leaks into the subcutaneous tissue Subcutaneous emphysema Authors: Lauren Hampton Reviewers: Kening (Midas) Kang Natalie Morgunov Sadie Kutz Usama Malik Leila Barss* * MD at time of publication Thoracic Ischemia endometriosis Mechanical forces of respiration create blebs Inflammation disrupts mesotheial and/or bullae ~ cell layer of the visceral pleura 47 Spontaneous rupture of blebs or bullae 47 Sudden onset pleuritic chest pain 71r Primary spontaneous pneumothorax: Presence or introduction of air in the pleural space in a patient WITHOUT diagnosed or clinically apparent lung disease Tachycardia Abbreviations: Communication occurs between the alveoli and pleural space • FLCN- Folliculin gene • HCY- Homocystinuria • MFS- Marfan syndrome Alveolar pressure > pleural pressure • CTD- Connective tissue disease • PSP- Primary spontaneous Air from the lungs enters the pleural space pneumothorax • V/Q- ventilation/perfusion Air separates the chest from /1` intrapleural pressure • Sp02- oxygen saturation the lung parenchyma Small areas of lung collapse Blood flow to areas of On affected side: under un-opposed intrinsic atelectasis is maintained -• Si, chest wall expansion elastic recoil while ventilation 4, t resonance to percussion Si, or absent tactile fremitus Si, or absent breath sounds 4, lung compliance Shunting and V/Q mismatch Pleural line on chest x-ray 1` work of breathing Tension pneumothorax* Accessory muscle use, 4• Sp02, Sudden onset dyspnea, Tachycardia Hypotension, Juglar venous Tachypnea distension, Pulsus paradoxus

Asthma Acute Exacerbation: Pathogenesis and Treatment

Asthma Acute Exacerbation: Pathogenesis and Treatment Viral URI Allergen Pollution Other Triggers Activation of immune system: Epithelial chemokine activation, lymphocyte activation, macrophage activation, t leukotriene production Inflammation of lower airway • Dyspnea Air flows past inflamed airways causes t irritation Cough and wheezing Release of inflammatory mediators Mucosal edema causing turbulent air flow 7Ir Wheezing Notes • Asthma: Airway hyper-responsiveness causing airflow obstructions • Acute Exacerbation (Asthma): An episode of increased symptoms due to decreases in airflow Abbreviations • PCO2: Partial pressure of CO, in arterial blood • PEF: Peak expiratory flow • SABA: Short-acting beta-2 agonists • Sp02 : Blood oxygen saturation level Mild to moderate exacerbation: PEF 50% of predicted Titrate O2 toSpO2, 92%, give SABA & steroids ■ Good response: symptoms resolved, PEF > 80% [Treat at home with SABA as needed and steroids Dyspnea Bronchoconstriction 1` Residual volume and 1` PCO2 Respiratory failure 1` Air trapping causes '1' intra-alveolar pressure Severe exacerbation: PEF 50% of predicted Educate patient regarding medications, Loss of Pulsus inhaler technique & [consciousness paradoxus follow up with primary care provider I Legend: Pathophysiology Mechanism Titrate O2 to402 93%, give SABA, steroids & magnesium sulfate Sign/Symptom/Lab Finding {Worsening symptoms and/or respiratory failure: Do not delay intubation, send to ICU, give SABA, steroids & magnesium sulfate Authors: Luke Gagnon Reviewers: Midas (Kening) Kang Usama Malik Lian Szabo* * MD at time of publication 4, Delivery of oxygen rich air to alveoli 4, Oxygenation of blood Drowsy and confused Central cyanosis • Tachycardia Pneumothorax [Depending on 1 severity: Observation or place chest tube

Bronchiectasis Pathogenesis and clinical findings

Bronchiectasis: Pathogenesis and clinical findings Acquired immunodeficiency Lymphoma, HIV, transplant Autoimmune Lupus, inflammatory bowel disease, rheumatoid arthritis Congenital/Genetic Cystic fibrosis, A1AT deficiency, Marfan, immunoglobulin deficiency, Kartagener syndrome, Young syndrome Endobronchial obstruction Neoplasm, foreign body, lymph node compression Other Inhalation exposure (smoke, ammonia), MAC complex infection, COPD, allergic bronchopulmonary aspergillosis, chronic infections Irreversibly dilated bronchi Chronic bronchial infection and inflammation 1 Easily collapsible airways I Bronchiectasis (persistent and progressive damage to lungs) Chronic cough (mucopurulent) Defect in immunity and/or mucus clearance Persistent bacteria in airway (commonly Pseudomonas/Staph aureus) Inflammatory response Rhinosinusitis Abbreviations: • A1AT — Alpha-1-antitrypsin • COPD — Chronic Obstructive Pulmonary Disease • HIV — Human Immunodeficiency Virus • MAC — Membrane Attack Complex • VQ— Ventilation/Perfusion ratio Legend: Pathophysiology Mechanism Fever Sign/Symptom/Lab Finding Failure to thrive (children) Authors: Rebecca (Becky) Phillips Reviewers: Midas (Kening) Kang Usama Malik Eric Leung* * MD at time of publication Notes: • Can be focal (single lobe/segment) or diffuse (both lungs) • Mainly in elderly • 1% prevalence in children Tissue damage Epithelial destruction of airways Further impairment of bacterial clearance Persistent inspiratory adventitious sounds (crackles > wheezing) Complications Structural damage to bronchial walls Obstructive pulmonary function tests Hemoptysis Chest pain VQ mismatch and 4, gas exchange 4, oxygenation Digital clubbing (rare) Fatigue Dyspnea Cyanosis (uncommon)

Benign Prostatic Hyperplasia: Pathogenesis and medications

Benign Prostatic Hyperplasia: Pathogenesis and medications Aging Testosterone Testosterone metabolized into DHT by type II 5- a-reductase in prostate DHT binds to androgen receptor in prostate cell nuclei Hyperplasia of the prostate Prostate encapsulated by fibromuscular tissue, therefore grows inwards Prostatic urethral compression and bladder outlet obstruction Legend: a-1 blockers (e.g. tamsulosin) Note: MoA not fully established PDE-5 inhibitors (e.g. tadalafil) Bladder and prostate smooth-muscle a-1 receptor antagonism —110. Relaxation of bladder outlet and prostate smooth-muscle Authors: Michael Korostensky Reviewers: Alex Tang Usama Malik Dr. Jay Lee* * MD at time of publication Acronyms: 5-ARI = 5-a reductase inhibitors COX = cyclooxygenase DHT = dihydrotestosterone GnRH = gonadotropin-releasing hormone LUTS = lower urinary tract symptoms PDE-5-mediated cGMP degradation in prostate smooth-Improved urinary outflow muscle and associated vascular supply Relaxation of prostate smooth-muscle MoA = mechanism of action NSAID = nonsteroidal anti-inflammatory drugs PDE-5 = phosphodiesterase-5 -NO 5-ARIs (e.g. dutasteride) LHRH receptor antagonists (e.g. cetrorel ix) P3-adrenergic agonists (e.g. mirabegron) anticholinergics (e.g. oxybutynin) NSAIDs 1` Bladder pressures Pathophysiology Mechanism 5-a-reductase activity 1, Conversion of testosterone into DHT 4, Progression of LUTS 1, Testosterone secretion from testicular Leydig cells 1, LH secretion from pituitary GnRH antagonism DHT production Relaxation of detrusor Bladder muscle 1` capacity Improved LUTS Acetylcholine antagonism at muscarinic receptors Relaxation of bladder outlet smooth-muscle 1` volume to first detrusor contraction 4, Prostaglandin release Analgesia and 4, Prostatic ,f, COX activity ► inflammation —110. Bladder smooth-muscle hyperplasia (detrusor thickening) /1` Sensitivity (i.e. overactive detrusor) -1110. 1, Volume to first detrusor contraction LUTS

Celiac Disease: Pathogenesis and clinical findings

Celiac Disease: Pathogenesis and clinical findings Associated with other autoimmune disorders (i.e. DM1, thyroiditis, RA, SLE, Addison's) Genetic predisposition -■ (Northern European, Down's syndrome, Associated with HLA DQ 2,8) Note: *The anti-TTG antibody is an IgA anti-body, therefore if the patient is IgA-deficient, absence of anti-TTG does not rule out celiac Anti-TTG in serum* Anti-TTG reacts with TTG in skin Deposition of anti-TTG in renal glomeruli Dermatitis herpetiformis Chronic Kidney Disease Small Bowel Biopsy: Crypts of bowel become enlarged (hyperplasia) with architectural change, villous shortening Legend: Pathophysiology Mechanism Exposure to prolamins (proteins found in wheat, rye, oats, barley) TTG alters prolamin Altered protein fits more easily into HLA HLA activates adaptive immunity IgA generated against prolamin-TTG Wheat prolamin (gliandin) interacts with and activates zonulin signalling Gut epithelium becomes more porous Large dietary proteins in epithelium disrupt tight junctions Author: Matthew Harding Yan Yu Peter Bishay Reviewers: Dean Percy Jason Baserman Usama Malik Kerri Novak* * MD at time of publication Inflammation of Intestinal epithelium Inflammation disrupts structure of bowel mucosa Mechanism Unknown Lymphocytes migrate to site of inflammation Extraintestinal Complications: Arthropathy Ataxia (gluten associated) Infertility Mild Hepatitis Villi of intestine atrophy Risk of Microscopic Colitis (50x) Malabsorption Extraintestinal manifestations: Chronic watery Fatigue Failure to thrive, weight loss Anemia (Fe, B12, folate) Peripheral neuropathy (B12, Ca) Ataxia (Ca) Dysrhythmia (Ca, K) Osteoporosis (Vit D, Ca) diarrhea + Intestinal manifestations steatorrhea: Pale, foul-smelling Abdominal bloating Steatorrhea (fat in stool) Diarrhea

Orbital Cellulitis: Pathogenesis and clinical findings

Orbital Cellulitis: Pathogenesis and clinical findings Authors: Amanda Marchak Reviewers: Jaimie Bird Dr. Rupesh Chawla* * MD at time of publication Staphylococcus aureus, Streptococcus pyogenes Note: Orbital cellulitis is an extremely serious infection. If not caught and treated early, it can lead to death. CT should be performed if suspected. Involves the orbit Panopthalmitisb Endopthalmitisc Blindness Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenza Local infection or break in skin Eye surgery or trauma Direct inoculation Sinusitis (more common) Periorbital cellulitis1,2 Hematogenous spread Contiguous spread of infection Pathogens reach orbital tissue (posterior to the orbital septum) Spreads to periorbital tissue (anterior to the orbital septum) Localized inflammation Conjunctival chemosisa Eyelid and periorbital edema Pain on palpation Induration Warmth Orbital Cellulitis Inflammation of orbital tissue Proptosis Spreads to surrounding structures Subperiosteal abscess Brain abscess Cavernous sinus thrombosis Meningitis Subdural empyema Orbital abscess Notes: Impinges on ocular muscles Impaired extra- ocular movements Pain with eye movement or opthalmoplegia Definitions: Impinges on nerves Afferent pupillary defect Decreased visual acuity Exposes cornea Corneal drying and scarring a. Chemosis: Edema of the bulbar conjunctiva b. Panopthalmitis: inflammation of all coats of the eye including intraocular structures. c. Endopthalmitis: inflammation of the interior of the eye. 1. See slide on Periorbital Cellulitis for how sinusitis can lead to the development of periorbital cellulitis 2. The micro-organism responsible for periorbital cellulitis varies depending on how the pathogen was introduced to the system. Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 5, 2018 on www.thecalgaryguide.com

Periorbital Cellulitis: Pathogenesis and Clinical Findings

Periorbital Cellulitis: Pathogenesis and Clinical Findings Authors: Amanda Marchak Reviewers: Jaimie Bird Dr. Rupesh Chawla* * MD at time of publication Staphylococcus aureus, Streptococcus pyogenes (most common organisms) Note: Also referred to as preseptal cellulitis Dacryoadenitisa Conjunctivitisb Acute chalazionc Dacryocystitisd Hordeolume Streptococcus pneumoniae, Moraxella catarrhalis, non-typable Haemophilus influenza (most common organisms) Abrasion Insect bite Burns Trauma Local infection Contiguous spread of infection Sinusitis Otitis media Hematogenous spread Local break in skin Micro-organisms enter Definitions: Note: Eye exam should reveal normal: - extra-ocular movements and globe position - pupillary reflex and visual acuity If any are abnormal, the presentation is no longer considered periorbital cellulitis, as the infection has likely spread beyond the preseptal compartment/orbital septum. If the eye cannot be assessed, the patient NEEDS a CT scan. Pathogens reach dermis and subcutaneous periorbital tissue Periorbital Cellulitis a. Dacryoadenitis: infection of the lacrimal glands b. Conjunctivitis: inflammation of the conjunctiva c. Chalazion: a benign, painless bump or nodule inside the upper or lower eyelid which results from healed internal hordeolums that are no longer infectious. d. Dacryocystitis: an infection of the lacrimal sac, secondary to obstruction of the nasolacrimal duct at the junction of lacrimal sac. e. Hordeolum: localized infection or inflammation of the eyelid margin involving hair follicles of the eyelashes or meibomian glands. Spreads beyond preseptal compartment/orbital septum Involves the orbit Orbital cellulitis See slide on Orbital Cellulitis: Pathogenesis and clinical findings Localized inflammation Pain on palpation Induration Warmth Eyelid and periorbital edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 5, 2018 on www.thecalgaryguide.com

Mastoiditis: Pathogenesis and clinical findings

Mastoiditis: Pathogenesis and clinical findings Authors: Amanda Marchak Reviewers: Nicola Adderley Jim Rogers Emily Ryznar Danielle Nelson* * MD at time of publication Acute Otitis Media (AOM) Distal middle ear is physically connected to mastoid air spaces Pathogens spread from middle ear to the mastoid air spaces Mucosa lining the mastoid becomes inflamed Mastoiditis 1 Infection persists Accumulation of pus in mastoid cavities ↑ pressure Formation of abscess cavities Dissection of pus into adjacent areas Infection spreads Into intracranial compartment See slide on Acute Otitis Media (AOM): Pathogenesis and Clinical Findings in Children Post- operation Trauma Infection Notes: 1. Most common suppurative complication of AOM Tenderness, erythema, swelling and fluctuance over the mastoid process Inflammation spreads to external auditory canal Cranial Nerve VII anatomically near mastoid Cranial Nerve VIII anatomically near mastoid air space Destroys bony septae b/t air cells (visible on CT) Mastoid abscess Swelling of external auditory canal Mastoid inflammation disrupts nerve Mastoid inflammation disrupts nerve Petrositis Facial nerve palsy Sensorineural hearing loss Labyrinthitis Osteomyelitis of the calvaria Into adjacent bones Underneath the periosteum Subperiosteal abscess Pinna is pushed out and of the temporal bone Into the neck beneath the attachment of the sternocleidomastoid and digastric muscles forward Dural venous thrombosis Temporal lobe abscess Meningitis Epidural abscess Subdural abscess Cerebellar abscess Bezold abscess Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 5, 2018 on www.thecalgaryguide.com

Sinusitis: Pathogenesis and clinical findings

Sinusitis: Pathogenesis and clinical findings Authors: Amanda Marchak Reviewers: Nicola Adderley Jim Rogers Danielle Nelson* * MD at time of publication Abbreviations URTI – Upper respiratory tract infection Nasal obstruction/ congestion Hyposmia Headache Facial pain/pressure Maxillary tooth pain Ear pain/ fullness Osteomyelitis of frontal bone Chemical irritants Cystic Fibrosis Direct toxic effect on cilia Viral URTI Allergies Inflammation of paranasal sinuses Edematous passageways Septal deviation Adenoid hypertrophy Polyps Turbinate hypertrophy Tumors Foreign body Dysfunctional cilia Congenital and/or craniofacial abnormality Obstruct sinus ostia Cilia unable to clear mucus from sinuses Mucus unable to drain through ostia Post-nasal drip Mucus overflows from the sinuses Cough Mucus accumulates in sinuses Occupies a larger volume Applies ↑ pressure to sinus walls Mucopurulent discharge Bacterial1 overgrowth in sinuses Bacterial infection spreads to adjacent structures Halitosis Pharyngitis Throat clearing Dental root infection Immunodeficiency Note: Irritates the back of the throat Perforation of the Schneiderian membrane2 Passage of bacteria into the sinuses Fever Fatigue Subperiosteal orbital abscess Orbital abscess Orbital edema ↑ susceptibility to bacteria 1. The most common bacteria are Streptococcus pneumoniae, Haemophilus influenza, and Moraxella catarrhalis. Staphylococcus aureus and Group A Streptococcus may be seen, but are less common. However, in cases of dental root infection, oral anaerobes become more common, while Pseudomonas species are associated with foreign bodies. 2. The Schneiderian membrane is the membranous lining of the maxillary cavity. Cavernous sinus thrombosis Meningitis Cerebral abscess Subdural abscess Epidural abscess Periorbital or orbital cellulitis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 5, 2018 on www.thecalgaryguide.com

Venous insufficiency- Signs and symptoms

Venous insufficiency- Signs and symptoms vein veins blood flow interruption venous system valve incompetence reflux venous obstruction venous return backflow blood hypertension hydrostatic transmural pressure in postcapillary vessels capillary dilatation vessel permeability extravasation RBCs interstitial hemoglobin released degraded hemosiderin deposits hemosiderosis brown discolouration high pressure superficial venous circulation varicose veins tortuous dilated superficial veins distended veins compress somatic nerves achy pain protein-rich exudate edema peripheral ankle edema tissue perfusion metabolic exchange stasis dermatitis dermal fibrosis lipodermatosclerosis fibrotic thickened skin pruritus chronic inflammation risk of thrombus local ischemia embolus skin integrity venous ulcer risk of infection Adderley gagnon Waechter

Reactive Neutrophilia- Pathogenesis and Clinical Findings

reactive neutrophilic pathogenesis clinical findings infection inflammation malignancy drugs emotional stimuli stress smoking hyposplenism asplenia rheumatoid arthritis Crohn's epinephrine retinoic acid glucocorticoids anxiety exercise heat stroke surgery neutrophils neutrophil bone marrow demarginalization splenic sequestration neutrophilic ANC peripheral blood smear absolute neutrophil count left shift bands metamyelocytes myelocytes toxic granulations dohle bodies brenneis Siddique savoie ryznar

Primary Myelofibrosis pathogenesis and clinical findings

Primary Myelofibrosis: Pathogenesis and clinical findings Legend: Published March 30, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com Author: Tony Gu Reviewers: Naman Siddique Sonia Cerquozzi* Man-Chiu Poon* * MD at time of publication Definitions: Constitutive activation – Constant expression of gene Extramedullary hematopoeisis – red blood cell production outside of bone marrow Somatic mutations in genes that drive cancerous replication (e.g., JAK2, CALR, MPL) within hematopoietic stem cells Non-driver mutations in other myeloid genes (e.g., LNK, CBL, TET2, ASXL1, IDH) Constitutive activation of cellular proliferation pathways ↑ cell signaling ↑ gene transcription and expression Cellular proliferation and resistance to apoptosis Proliferation of abnormal megakaryocytes ↑ neutrophil engulfment by megakaryocytes ↑ growth factor release by megakaryocytes Stimulation of fibroblasts Stimulation of endothelial cells New blood vessel formation ↑ osteoprotegerin Unbalanced osteoblast proliferation Osteosclerosis Fibrosis of the bone marrow Anemia Bleeding and bruising Infections Fatigue and pallor Bone pain Increased cell turnover Tumor lysis syndrome Cachexia, night sweats, fever/chills, malaise Expanding marrow pushing against bone Extramedullary hematopoiesis Hepatomegaly Portal hypertension Splenomegaly ↑ LDH Thrombocytosis Leukocytosis Secretion of coagulation inducing cytokines Arterial and venous thromboembolism ↓ blood cell production & leukoerythroblastosis Thrombocytopenia Leukopenia ↑ K+, PO4 2-, uric acid ↓ Ca2+ Bone pain Periostitis Immature granulocyte and erythroid precursors with blasts ↑ cytokine production (+) ↑ sequestration of blood cells Disseminated intervascular coagulation (see MAHA slide) Definitions: Periostitis – Inflammation of the membrane surrounding bone Osteosclerosis – Abnormal hardening and increased in density of bone

Hemorrhoids - Pathogenesis and Clinical Findings

INTERNAL Hemorrhoids - Found proximal to the dentate line - Visceral innervation Behavioural or Genetic Predisposition I.e. hereditary bowel/rectal problems or shared habits and practices (unclear mechanism) Increased Intra-Abdominal Pressure I.e. pregnancy, constipation, chronic straining, lifting, cirrhosis Hemorrhoids: Pathogenesis and clinical findings Dilations originate from inferior hemorrhoidal venous plexus Vascular cushions engorge along anal canal Legend: Published March 30, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com Authors: Aleeza Manucot Reviewers: Yoyo Chan Sean Doherty Dr. Sylvain Coderre* * MD at time of publication Supporting tissues of anal cushions weaken, disintegrate, or deteriorate Inflammatory reaction occurs, involving vascular wall and connective tissue Thrombosis Pain ↑ mucus secretions or fecal soiling of prolapsing hemorrhoids Cushion epithelium erodes via damage from compression Painless rectal bleeding Bleeding without prolapse Prolapse with spontaneous reduction Prolapse requiring manual reduction Irreducible 1st degree 2nd degree 3rd degree 4th degree Infarction and thrombosis Acute severe pain Anal cushions prolapse (downwardly slide) into rectum or open space Dentate line: divides the upper two thirds and lower third of the anal canal EXTERNAL Hemorrhoids - Found distal to the dentate line - Somatic innervation Somatic nerve receptors activated Sebaceous glands ↑ secretions around area of hemorrhoid Itching Perianal irritation Swelling Inflammation creates prothrombotic state Hemorrhoids

gastroesophageal-reflux-disease-gerd-complications

Gastroesophageal Reflux Disease (GERD): Complications Esophageal stricture disease Esophagitis Esophageal adenocarcinoma Barrett’s esophagus GERD Reflux of gastric content into distal esophagus Damage to squamous esophageal epithelium Legend: Published March 30, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com Authors: Wendy Wang Reviewers: Yoyo Chan Sean Doherty Dr. Sylvain Coderre* * MD at time of publication Squamous esophageal epithelium undergoes metaplasia to become columnar epithelium This predisposes cells to premalignant changes (dysplasia) Collagen is deposited where ulcers heal Asthma/Chronic Cough Chronic Laryngitis Laryngeal and Tracheal Stenosis Extra-esophageal Complications Esophageal Complications Airway becomes irritated Fibroblasts proliferate and deposit granulation tissue in airway Tissue deposition leads to narrowing of laryngeal and tracheal space Damage to pharyngeal lining and airway Esophageal tissue repeatedly exposed to stomach acid Pro-inflammatory cells and cytokines are recruited to the area Definitions: • Metaplasia: abnormal change in the nature of a tissue • Pro-inflammatory cells and cytokines: Mediators of inflammation. Examples of cells include macrophages and T cells, cytokines include IL-17, IL-2, IL-4 Over time, collagen fibers contract Bronchoconstriction ↑ vagal tone ↑ bronchial reactivity Cough sensory nerve endings are stimulated Vagal reflex is activated Activation of cough center in brainstem ↑ inflammation of squamous epithelium Ulcers form in esophagus

Polyarteritis Nodosa (PAN): Pathogenesis and Clinical Findings

Polyarteritis Nodosa (PAN): Pathogenesis and clinical findings Environmental triggers Infectious/viral agents (commonly Hepatitis B) Medical Comorbidities Malignancies (most commonly hairy-cell leukemia) Immunogenetic Predisposition: patient is genetically predisposed to a dysregulated immune response Fever ↑ ESR and CRP Postulate 1 Viral antigen-antibody complexes deposit in vasculature, causing lesions and activating cellular inflammatory response Authors: Nela Cosic, Yan Yu* Reviewers: Sean Doherty Martin Atkinson* * MD at time of publication Palpable or necrotic purpura Malignant Hypertension Renal Insufficiency Myocardial ischemia Heart failure Diffuse myalgias Postulate 2 Viral replication causes direct injury to vascular endothelial cells ↑ Anti- endothelial cell autoantibodies (AECA) Altered cytokine profile (↑TNF-α, IL-1β, IFN-α, IL- 2)à↑ T-cell mediated immune response Weight metabolism Loss Autoimmune attack on various areas of the body Malaise and/or Arthralgias (knees, ankles, elbows, wrists) Orchitis: Testicular pain, erythema and/or swelling Small intestine perforation GI Manifestations Non-specific abdo pain GI hemorrhage Peripheral sensory changes: Distal mononeuropathy multiplex Polyarteritis Nodosa (PAN) Focal segmental necrotizing leukocytoclastic vasculitis of medium or small-sized arteries Inflammation of arteries damages the vascular endothelium of those arteries Inflammation predisposes formation of arterial thromboses Blockage of arteriesà tissue ischemia and possible necrosis (tissue cell death) ↑ basal Arterial aneurysms Inflamed subcutaneous arteries Inflamed renal artery àluminal narrowing and reduced blood flow to kidneys Inflamed coronary artery à luminal narrowing, occlusion, thromboses Segmental inflammation of muscular arteries, stimulating surrounding nociceptors. Muscle ischemia develops long-term. Ischemia/necrosis of the testicles Ischemia/necrosis of the small intestine Ischemic vasculitic nerve damage: Immune complex deposition within vessel walls of arteries traveling with nerves leads to persistent vascular inflammation and ischemia of associated nerve Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 18, 2019 on www.thecalgaryguide.com

Crohn's Disease

Inflammatory Bowel Disease: Clinical findings in Crohn’s Disease Authors: Yan Yu Amy Maghera Reviewers: Jennifer Au Danny Guo Jason Baserman Jessica Tjong Kerri Novak* * MD at time of publication Behavioural Factors: Smoking, over-sanitation Genetic Susceptibility Environmental Factors Diet, bacteria/viruses, drugs, vitamin D Systemic immune response primarily against the GI tract. (Unclear mechanism, mediated by cytokine release and neutrophil inflammation) Inflammation of the GI tract lining - Inflammation is “transmural”, spanning the entire thickness of the intestinal wall from luminal mucosa to the serosa. - The inflammation occurs anywhere in the GI tract from the oral mucosa to the anal mucosa (from ‘gums to bum’) in skip lesion pattern. Atrophy, scarring of the intestinal villi Inflammatory cytokines destroy the mucosa epithelial cells of the GI tract wall, causing cell apoptosis and ulceration ↑ permeability of the blood vessels supplying the GI tract wall Chronic inflammation impairs healing responses Dysregulated wound healingàexcess extracellular matrix deposition Fibrosis leads to scar tissue and thickening of all layers of the GI tract Strictures Inflammation is systemic, affecting: Joints Arthropathy Erythema Impaired absorption of nutrients Weight loss Prolonged GI bleeding Anemia Transporter proteins responsible for Na+ reabsorption gradually disappear from the epithelium More sodium (and thus water) is retained in the GI tract lumen Microperforations can penetrate through the intestinal wall Anal fistulae (“holes” connecting the anus to the skin, bladder, peritoneum, small bowel, etc.) Continued inflammation and/or infection can lead to: Leakage of fluid out of capillaries into the GI tract Luminal edema and swelling Narrowing of GI lumenàbowel obstruction Skin Mouth Eyes Liver nodosum, pyoderma gangreno- sum >5 canker sores Uveitis Iritis, scleritis Sclerosing cholangitis ↓ fat absorption Fatty acids (negatively charged) bind Ca2+, freeing oxalate from Ca2+ ↑ oxalate absorbed into blood & filtered by kidney Calcium oxalate kidney stones Diarrhea Abdominal cramping and pain (see Bowel Obstruction page for full mechanism Anal abscesses Inflammatory masses Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published June 15, 2019 on www.thecalgaryguide.com

Ulcerative Colitis

Inflammatory Bowel Disease: Clinical Findings in Ulcerative Colitis Authors: Yan Yu Amy Maghera Reviewers: Jennifer Au Danny Guo Jason Baserman Crystal Liu Danielle Chang Kerri Novak* * MD at time of initial publication Inflammation is systemic, affecting: Environmental Factors Diet, bacteria/viruses, drugs Genetic Susceptibility Behavioral Factors: In UC, smoking and appendectomy are actually protective (unknown reason) Immune response against the GI tract. (Unclear mechanism, but thought to be mediated by cytokine release and neutrophil infiltration) Inflammation of the GI tract epithelial lining - Starting at the rectum and moves up the colon and is continuous (does not invade the small intestine) - Inflammation affects the mucosal and submucosal only Diarrhea, abdo pain and cramping causing avoidance of food Weight loss Apoptosis of GI tract mucosa Transporter proteins responsible for Na+ reabsorption gradually disappear from the epithelium Ulceration, into the anus, and more severe Prolonged Bleeding - GI and anus Anemia, often iron deficiency Inflammation ↑ permeability of the blood vessels supplying the GI tract wall Fluid leak out of capillaries into GI tract wall, causes edema and swelling Swelling narrows the GI tract lumen, causing bowel obstruction Inflammation, ulceration, or infection at the anus (all involve the RECTUM!) Anal irritation stimulates autonomic and somatic nerves leading up to the brain, causing the pt to want to defecate Tenesmus, urgency, frequency (feeling or urgency to defecate, but little stool is produced) Joints Skin Arthroplasty/ joint pain Erythema nodosum, pyoderma gangrenosum Mouth >5 canker sores More sodium (and thus water) is retained in the GI tract lumen Bloody Diarrhea, usually bloody due to anal bleeding and ulceration bleeding Abdominal Cramping and pain (see Bowel Obstruction page for full mechanism) Eyes (uvea, iris, sclera) Liver Blood Uveitis Iritis, scleritis Sclerosing Cholangitis Autoimmune hemolytic anemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published May 5, 2019 on www.thecalgaryguide.com

perforated-viscous

Perforated “Viscous” (aka. GI tract; bowels): Author: Yan Yu Reviewers: Michael Blomfield, Tony Gu, Dean Percy, Danny Guo Maitreyi Ramran* * MD at initial time of publication Chest X-Ray (CXR) Pathogenesis and Clinical Findings Diverticulitis Crohn’s disease Peptic ulcer (H. pylori infection, NSAID use, ICU stress, etc) Appendicitis Malignant neoplasm Irritates visceral peritoneum, stimulates autonomic nerves Severe inflammation causes destruction of GI tract mucosa Over time, Perforation of the GI tract wall Bowel contents (air, fluids) released into peritoneal cavity Massive peritoneal inflammation Diagnostic investigations if a GI perforation is suspected Dull diffuse abdominal pain Severe, Sharp abdominal pain with peritoneal signs Abdominal X-ray Irritation of parietal peritoneum, stimulates somatic nerves • Abdominal X-ray • Intra-peritoneal air will coat the GI tract surfaces, giving them a faint white outline under X-ray • Chest X-ray of upright patient (Diagnostic) • Intra-peritoneal air will rise above the peritoneal fluid when pt is upright, accumulating under the right hemi-diaphragm. • Note: air under left hemi-diaphragm = normal gastric bubble • CT? Most patients with suspected GI perforation will get a CT scan, but this is not the diagnostic gold standard (and access to CT can be limited, especially in rural settings) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published June 30, 2019 on www.thecalgaryguide.com

acanthosis-nigricans-pathogenesis-and-clinical-findings

Acanthosis Nigricans: Pathogenesis and clinical findings Authors: Laura Chin Reviewers: Taylor Woo Crystal Liu Laurie Parsons* * MD at time of publication Medications E.g. systemic glucocorticoids, injected insulin, oral contraceptives Hyperinsulinemia Insulin inhibits IGFBP 1&2 secretion Genetic Syndromes E.g. Down syndrome, Rabson- Mendenhall syndrome, congenital generalized lipodystrophy Defects in insulin receptor or anti-insulin receptor antibody production Insulin Resistance ↑ IGFR1 binding Type 2 Diabetes Mellitus Polycystic Ovarian Syndrome Obesity Neoplasms E.g. gastric carcinomas Excess IGF-1, TGFα, and FGF production TGFα is structurally similar to EGFα TGFα can bind to EGFR ↑ EGFR binding Inheritable Mutations E.g. FGFR3 activating mutation ↑ free IGF-1 ↑ FGFR binding Moist environment and rubbing of intertriginous skin Skin inflammation and thinning Bacterial or yeast infection Erosions Malodour Dermal keratinocyte and fibroblast growth and differentiation of neck and intertriginous areas, occasionally mucosal surfaces Hyperkeratosis Abbreviations: • IGF-1 – insulin-like growth factor • IGFR1 – insulin-like growth factor receptor-1 • IGFBPs – insulin-like growth factor binding proteins • FGFR – fibroblast growth factor receptor • TGFα – transforming growth factor-alpha • EGFα – epidermal growth factor-alpha • EGFR – epidermal growth factor receptor Hyperpigmentation Crusting Velvety plaques Pain Pruritis Pus Acanthosis Nigricans Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 14, 2019 on www.thecalgaryguide.com

Appendicitis

Appendicitis: Pathogenesis and Clinical Findings Authors: Yan Yu Wayne Rosen* Reviewers: Wendy Yao Laura Craig Noriyah AlAwadhi* * MD at time of publication Dull, crampy, diffuse peri- umbilical pain Pt may develop fever, diarrhea, constipation, vomiting or anorexia as inflammation worsens Focal, intense, persistent RLQ pain, abdominal guarding and peritoneal signs (i.e. percussion and rebound tenderness Epidemiology Dx of healthy adults: • Men > women • Commonly 10-30 years old, can present at any age • Most common cause of acute abdomen (5% prevalence in all ethnicities) The appendix is anatomically located in the RLQ; appendicitis may be confused with disorders of surrounding structures: Gynecological Diseases • RuleoutpregnancywithHCG pregnancy test • Rupturedovariancyst • Ectopicpregnancy • Mittelschmerz(mid-cycle pain) Gastro-intestinal Diseases • Meckel’sdiverticulum (presents identically to appendicitis; surgically located 2 feet from ileocecal valve; mostly seen in children) • Diverticulitis(presentsasleft sided appendicitis) Non-GI Abdominal Issues • Mesentericadenitisinkids <15: swollen mesenteric lymph nodes • Renalcolic Obstruction of appendiceal lumen (by fecalith, fibrosis, neoplasia, foreign bodies or lymph nodes in kids) Appendix distension and spasms ↑ lumen pressure, ↓ blood flow to appendix Ischemia, tissue necrosis, loss of appendix structural integrity Bacterial invasion of the appendix wall, causing transmural inflammationandnecrosis Stretching of visceral peritoneum, stimulation of autonomic nerves T9-T10 Progression of inflammation over several days (variable length of time) Irritation of parietal peritoneum, stimulation of somaticnerves If appendix not surgically removed Perforation of colon wall, causing peritonitis, abscesses or death Note: Symptoms hugely variable. Only 30% present with classic history. Diagnosis is mostly clinical. Further investigations: CBC: Leukocytosis (due to inflammatory response) CT: Gold standard test. Thickened visceral membrane with enhancing (white) rim due to ↑ blood flow Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published July 27, 2019 on www.thecalgaryguide.com

Acute GI Related Abdominal Pain

Acute GI-Related Abdominal Pain: Pathogenesis and Characteristics Authors: Yan Yu Wayne Rosen* Reviewers: Laura Craig Danny Guo Julia Heighton Maitreyi Raman* * MD at time of publication Peritoneal cavity Visceral peritoneum (innervated by autonomic nerves) Bowel stretching, pulling, contracting Abdominal pain type: Diffuse, non-localized Dull, crampy, periodic Not associated with movement Patient may writhe around, trying to get rid of the pain Mesentery Intestinal lumen Parietal peritoneum (innervated by somatic nerves) Cross-section of the GI tract Cuts, structural damage, and inflammation in the bowel Important Notes • Acute abdominal pain can also result from non- gastrointestinal causes, such as kidney stones, female reproductive tract issues, and urinary tract issues. For simplicity’s sake, only the GI-related acute abdominal pain disorders are listed here. • The DDx of visceral abdominal pain is broad. Please consult relevant sections of the Calgary Black Book for the DDx. • Keep in mind that visceral abdominal pain can also be caused by the “acute abdomen” diseases (if the diseases are presenting in their initial phases). • • • • • • Abdominal pain type: Sharp, well-localized Excruciatingly painful, persistent Associated with movement of bowels Patient often lies still to avoid abdominal vibration Peritoneal signs Abdominal guarding, pain with abdominal vibration (coughing, shaking, percussion, palpation) Transition from diffuse to localized pain can indicate disease progression (e.g. from visceral to parietal peritoneal inflammation) Note: bowel obstruction may or may not present as acute abdominal pain Bowel Infarction Appendicitis Diverticulitis Acute Cholecystitis Acute Pancreatitis Perforated Ulcer DDx of an “acute abdomen”: A sudden, non-traumatic disorder of the abdomen that needs urgent diagnosis and treatment. Each topic will be further explored in their respective slides. Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published July 27, 2019 on www.thecalgaryguide.com

virchows-triad-and-deep-vein-thrombosis-dvt

Suspected Deep Vein Thrombosis (DVT): Authors: Dean Percy Yan Yu Reviewers: Tristan Jones Ryan Brenneis Man-Chiu Poon* Maitreyi Raman* * MD at time of publication Pregnancy, Oral Contraceptives (OCP) Pathogenesis and Complications Platelet Activation Increased clot formation Hypercoagulable State ↑ ability for the blood to coagulate upon stimulation Inherited Disorders Congenital defect in coagulation (ie. Factor V Leiden, Factor II mutation, Protein S/C deficiency) ↑ blood clotting ability Estrogen promotes hypercoagulability, especially in presence of other risk factors Notes: • Venous thrombus causes pulmonary embolism, arterial thrombus causes stroke • Previous DVT is risk factor for current DVT Trauma/Surgery Malignancy Abnormal release of coagulation-promoting cytokines Systemic injuryà activation of coagulation cascade Hypertension Bacteria Artificial Valve Physically damages blood vessel walls Adhere/invade vessel wall Abnormal surface Vessel Injury Exposes tissue factor on damaged cells and subendothelium for vWF binding Virchow’s Triad Venous Stasis Low blood flow rate over site of vessel injury, concentrating blood clotting factors at that site Fat contains more aromatase, converts more androgens to estrogen Sedentary lifestyle, poor venous return Obesity Clot formation typically occurs in leg veins Deep, large veins allow for blood pooling (stasis, hypercoagulability) Venous return from legs often against gravity (stasis) Valves in leg veins prone to backflow (stasis) ↓ muscle motion = ↓ venous blood flow Fracture, immobilization, bedrest, long vehicle/airplane ride Destruction of vein valve by clot Venous Insufficiency Clot prevents blood from returning to heart. Blood accumulating in the leg results in unilateral leg edema and venous inflammation (redness, warmth, tenderness) 1. 2. 3. Clot embolizes to the lungs Thromboembolus -*Pulmonary embolism (acute life threatening complication) -Chronic thromboembolic pulmonary hypertension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published September 1, 2019 on thecalgaryguide.com

Acute-Pancreatitis

Acute Pancreatitis: Pathogenesis and Clinical Findings Authors: Yan Yu Reviewers: Laura Craig Noriyah AlAwadhi Ryan Brenneis Maitreyi Raman* * MD at time of publication Associated signs due to intra- abdominal hemorrhage from an unknown mechanism (classically associated with pancreatitis, but happens in <1% of cases): Note: It is not enough to just diagnose “acute pancreatitis”. Full management requires determining underlying etiology with further work-up. Alcohol ↑ Toxic metabolites within pancreas and Spincter of Oddi Spasms Gallstones Migration to common bile duct blocks Sphincter of Oddi Hypertriglyceridemia Unknown mechanism (rare) Idiopathic Further investigations: CBC: Cell counts elevated, due to sever hypovolemia Serum [Lipase]: Gold Standard Diagnostic Test; rupture of pancreatic cells releases lipase into circulation Pancreatic secretions back up, ↑ pressure within pancreas Hypercalcemia (Rare; Ca2+ depositions in bile ducts block outflow of pancreatic secretions) Since pancreas is retroperitoneal, somatic nerves in the parietal peritoneum are directly stimulated Inflammation triggers cytokine release Inflamed pancreas irritates adjacent intestines, causing ileus Inflamed, more permeable blood vessels leak fluid into pancreas • • Cullen’s sign (bruising in peri-umbilical region) Grey-Turner’s sign (bruises along both flanks) Sudden, severe epigastric pain (with peritoneal signs), radiates to the center of the back Fever, nausea/vomiting (general signs of inflammation) Diminished bowel sounds Profound dehydration (flat JVP, hypotension, tachycardia, oliguria) – may happen, not always 1. Pressure compresses pancreatic blood vessels, causing tissue ischemia. 2. Activation of inactive proteases (zymogens) digesting pancreatic tissue Necrosis (death) of pancreatic cells Inflammation self- perpetuates Massive systemic inflammatory response 2 main complications, usually detected on CT; may happen, but not always 1. Pancreatic pseudocyst (enlargement of the pancreas due to fluid accumulation) 2. Pancreatic necrosis/abscesses (death of a part of the pancreas) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-published September 1, 2019 on thecalgaryguide.com

Endometritis

Endometritis: Pathogenesis and clinical findings Prolonged rupture of membranes > 24 hours between amnion rupture and delivery ↑Time for vaginal flora to ascend into the uterus Assisted vaginal delivery Use of forceps or vacuum Multiple digital vaginal exams Manual examination of the vagina to assess cervical dilation Internal monitoring Intrauterine device to monitor the fetus or contractions Group B Streptococcus colonization Opportunistic bacteria present in the normal vaginal flora of up to 30% of women Bacterial Vaginosis Overgrowth of anaerobic bacteria with associated decrease in protective Lactobacillus species Foreign bacterial ascension into the uterus Sepsis Cesarean delivery ↑ Exposure of vaginal flora to the uterus Introduction of bacteria directly into the uterus Spread of infection to myometrial and parametrial layers of uterus Authors: Gabrielle Wagner Reviewers: Danielle Chang Crystal Liu Aysah Amath* * MD at time of publication ↑ Susceptibility to bacterial invasion of the uterine lining Endometritis Postpartum infection of the uterine endometrial lining Activation of innate Fever, immune response Inflammation of uterus Leukocytosis Accumulation of WBCs within vaginal discharge Purulent or foul-smelling lochia (vaginal discharge) Uterine tenderness Pelvic and/or abdominal pain Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 26, 2019 on www.thecalgaryguide.com

Viral-Hepatitis

Viral Hepatitis: Pathogenesis and clinical findings Infection with a virus that targets the Authors: Sean Spence Tyler Anker Yan Yu Reviewers: Dean Percy Crystal Liu Sam Lee* * MD at time of publication liver, e.g. HAV, HBV, HCV, HDV, HEV Hepatocytes are invaded & damaged Foreign particles and tissue damage activate immune systemàliver inflammation Lysis (bursting) of hepatocytes Infection with chronic viruses (HBV and HCV) persist over time and additional symptoms may develop RUQ pain/tenderness If infection is prolonged or severe, inflammation becomes systemic Release of hepatocyte’s cellular contents into the bloodstream Infection with acute viruses (HAV and HEV) resolve over time, and the symptoms above normalize Notes: • HDV can only infect people with concomitant HBV infection • HAV and HBV vaccines are the only ones that currently exist • Not all patients with viral hepatitis will develop each of these symptoms. The presentations vary. Fever, nausea, vomiting ↑ serum ALT, AST ↓ Hepatic metabolic activity (e.g. reduction of gluconeogenesis) ↓Serum Glucose ↓ Synthesis of plasma proteins (albumin, clotting factors, etc) ↓ Albumin, ↑ INR Abbreviations: • HAV - Hepatitis A Virus • HBV - Hepatitis B Virus • HCV - Hepatitis C Virus • HEV - Hepatitis E Virus • RUQ - Right Upper Quadrant • ALT - Alanine Aminotransferase • AST - Aspartate Aminotransferase • INR - International Normalized Ratio ↓ Bilirubin clearance from blood, bilirubin ends up under the skin Jaundice Portal Hypertension Encephalopathy, Splenomegaly, Esophageal Varices, Ascites, Caput Medusae, Edema Encephalopathy, Muscle Wasting, Metabolic Bone Disease, Terry’s Nails, Ascites, Bruising, Clubbing, Edema Spider Nevi, Altered Hair Patterns, Testicular Atrophy, Gynecomastia, Palmar Erythema Progressive deterioration in liver function, possibly ending up in cirrhosis. (See slide on “Cirrhosis: pathogenesis and complications” for more details on mechanisms and full explanations.) Hepatic Insufficiency Hyperestrogenism Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published January 12, 2020 on www.thecalgaryguide.com

C5-C9-deficiency

C5-C9 deficiency: pathophysiology and clinical findings Authors: Heather Yong Reviewers: Jessica Tjong, Crystal Liu, Yan Yu*, Nicola Wright* * MD at time of publication Normal complement response The complement pathway is a non- specific response to bacterial pathogens Bacterial infection Classical, alternative, or lectin pathway activation Complement cascade MAC formation on bacterial surface C5b, C6, C7, C8, C9 Complement proteins create trans- membrane channels within bacterial cell walls/cell membranes Critical bacterial proteins leak out of the cell, breakdown of entire cell Primary (hereditary) causes Secondary (acquired) causes All are autosomal recessive Biologic therapy ex. eculizumab Absence or suboptimal functioning of Abbreviations: • MAC: Membrane Attack Complex • CH50: Classic Hemolytic Complement Test • AH50: Alternative Hemolytic Complement Test • CNS: Central Nervous System • CSF: Cerebrospinal Fluid ≥1 terminal complement proteins C5-C9 deficiency Inability to form MAC ↑ susceptibility to systemic Neisseria infection Commonly N. meningitidis Rarely N. monorrhoeae Nasopharyngeal colonization of N. meningitidis, ↑ susceptibility to bacteremia CH50 ± AH50 assay No lysis Note: Total complement activity assay <10% activity C5, C6, C7, C9 <50% activity C8 Varied bactericidal action via other complement proteins • Risk of invasive meningococcal disease is 1000-10000X higher in C5-C9 deficiency than in the general population • Reason is unknown • C5-C9 deficient patients are not at greater risk for contracting other gram (-) infections • Clinical meningitis in C5-C9 deficiency is less severe and fatality is rare Bacterial lysis Especially gram (-)ve bacteria like Neisseria Bacteria cross the blood-brain barrier, causing swelling and damaging brain tissue Fatigue, fever, headache, altered mental status, etc. Inflammation of CSF and meninges Activation of dura and pia mater fibres Headache, neck stiffness Bacteria release toxins Damage to surface blood vessels Maculopapular rash Exact mechanism unknown Recurrent meningitis CNS damage due Sepsis to recurrent meningitis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 16, 2019 on www.thecalgaryguide.com

Infarctus du myocarde: Antécédents médicaux

Infarctus du myocarde: Antécédents médicaux Infarctus du myocarde (nécrose 8ssulaire) Auteur: Yan Yu Traductrice: Olivia Genereux Réviseurs: Sean Spence Tristan Jones Nanette Alvarez* Marie Giroux* *MD au moment de publication Sang du ventricule gauche reflue à l’oreille[e gauche et finalement s'accumule dans le système vasculaire pulmonaire Haute pression du système vasculaire pulmonaire force fluide hors des capillaires et dans l'interstitium pulmonaire et les alvéoles Inflammation myocardique locale Médiateurs inflammatoires irritent les nerfs cardiaques (plexus cardiaque) ̄ Fonc8on systolique (myocarde nécro6que ne peut pas se contracter suffisamment) Invasion généralisée des cytokines inflammatoires Cytokines agissent les régulateurs de température hypothalamique Fièvre légère Irritation des nerfs sympathiques afférents (T1-T4) Signal entre moelle épinière, a/n dermatomes T1-T4 Cerveau perçoit irritation des nerfs comme douleur des dermatomes T1-T4 Douleur écrasante, pression, oppression de la poitrine: Souvent rétrosternale, avec radiation à épaule, cou et l'intérieur des deux bras (D>G) (Apparition: au repos, crescendo) IrritaNon des branches cardiaques du nerf vague AcNvaNon réponse vasovagale Fatigue, étourdissements, nausée, vomissement ↓ volume systolique (VS) ↓ debit cardiaque (DC) ­ Activité sympathique (pour essayer de maintenir DC) ­ Sueurs (diaphorèse) Peau moite VasoconstricNon généralisé Vasoconstriction des artérioles de peaux Peau froide Interstitium pulmonaire mou ↓ compliance pulmonaire d Fluide compresse les voies respiratoires, ↑ résistance au flux d’air Abrévia8ons: • a/n – au niveau À Noter: Douleur myocardique ischémique peut présenter différemment entre les patients, mais les symptômes récurrents habituellement présentent les mêmes pour un patient donné. Muscles respiratoires travaillent plus fort pour venNler les poumons Essoufflement (difficulté à respirer) Légende: Physiopathologie Mécanisme Signe/Symptôme/Résultats de Laboratoire Complications Publié Janvier 20, 2013 sur www.thecalgaryguide.com

acute-pancreatitis-complications

Acute pancreatitis: Complications Inflammation causes vasodilation and vasculature leakage Mild, (85%): Interstitial edematous pancreatitis Local accumulation of fluid in the pancreas <2 weeks after onset Acute peripancreatic fluid collection (not encapsulated) Walled off by fibrous & granulation tissue >2 weeks after onset Pancreatic pseudocyst (completely encapsulated) Peritoneal irritation à pain Large cyst can (very rarely) compress surrounding bowel Acute Pancreatitis Inflammatory cytokines are released from damaged pancreas If recurrentàchronic pancreatitis (see relevant slide) Inflammation damages pancreatic exocrine cellsàInappropriate release of pancreatic enzymes into surrounding tissue & vasculature àdigesting pancreatic parenchyma Authors: Nissi Wei, *Yan Yu Reviewers: Dean Percy, Miles Mannas, Varun Suresh, Brandon Hisey, *Kerri Novak, *Sylvain Coderre * MD at time of publication complete resolution (most cases) Necrotic tissue is vulnerable to infection (esp. Gram neg GI bacteria) inflammation & necrosis activate cytokine cascade Severe, necrosis (15%): Necrotizing pancreatitis Local infection Severe pancreatic inflammation shifts body fluid into retroperitoneal spaceàintravascular volume depletion Systemic Inflammatory Response Syndrome (SIRS) (see relevant slide) Organ failure (may be sole feature on presentation) Stagnant fluid can more easily become infected Infection spreads to bloodstream Cardiac failure Hypovolemic shock Renal failure Local accumulation of fluid & necrosis in the pancreas < 4 weeks after onset: Acute necrotic collection (not encapsulated) Walled off by fibrous & granulation tissue > 4 weeks after onset walled-off necrosis (completely encapsulated) When treated with excess fluid resuscitation: Intra- abdominal hypertension Respiratory failure (ARDS) Disseminated intravascular coagulation (DIC) Bowel obstruction Gastric outlet (see relevant slide) obstruction Infected pancreatic necrosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 20, 2016, updated September 7, 2020 on www.thecalgaryguide.com

Multiple-Sclerosis-on-Brain-MRI

Classic Findings of Multiple Sclerosis (MS) on Brain MRI Authors: Evan Allarie Davis Maclean Viesha Ciura* Reviewers: Yan Yu* * MD at time of publication infiltrates in the infratentorial region Note: variation in findings exist. The findings shown here are not exhaustive but are some of the most common areas implicated on brain MRI in MS. Most common sites that lesions are observed are: juxtacortical regions, periventricular, infratentorial, spinal cord, and the optic nerve. However lesions can occur anywhere there is myelin in the CNS. Active inflammation and destruction allows for gadolinium contrast to cross the blood- brain barrier, which can be visualized as a marker of active inflammation in MS Classic optic nerve (CN II) lesion seen in optic neuritis. Gadolinium enhancement (↑ signal intensity of lesion after gadolinium injection) in this T1 image demonstrates active inflammation Image Credits: Dr. Viesha Ciura For further pathogenesis, see the Calgary Guide slide: Multiple Sclerosis (MS): Pathogenesis and Clinical Findings Inflammation within the central nervous system (CNS) T-cell, B-cell, and macrophages infiltrate CNS Infiltration occurs through veinsàlocal inflammation Perivenular infiltrates around the medullary veins (perpendicular to ventricles) Inflammation and blood-brain barrier destruction ↑ extravascular inflammatory fluid around lesions, which appears hyperintense/bright Loss of neuronal/axonal density in affected region, replaced by gliosis over time Lesions extend out around veins, creating characteristic ovoid lesions Classic hyperintense T2/FLAIR perpendicular periventricular plaques following the medullary veins – ‘Dawson’s Fingers’ Middle cerebellar peduncle T2/FLAIR hyperintense lesion in classic location for MS Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 25, 2020 on www.thecalgaryguide.com

Bronchiolitis-updated

Bronchiolitis: Pathogenesis and clinical findings Viral pathogen, most commonly respiratory syncytial virus (RSV) - but can be others such as rhinovirus, adenovirus, parainfluenza, influenza, and coronaviruses - initially colonizes the nasopharyngeal mucosa Virus travels via the epithelium to the lower airways to the terminal bronchioles (small airways) Authors: Nick Baldwin Rebecca Lindsay Reviewers: Kayla Nelson, Yan Yu Timothy Fu, Danielle Nelson* *MD at time of publication Upper airway mucosal inflammation Bronchiolitis (bronchiole inflammation) Apnea (cessation of breathing; via unknown mechanism, potentially apnea reflex) RSV-fusion protein facilitates fusion of the virus to the host cell and directs viral penetration as well as facilitates fusion of the infected cell with its healthy neighbors Forms syncytia (multinucleated cells) Cytokines are released into circulation ↑ thermo- regulatory set- point at the hypothalamus Mild Fever Copious coryza (nasal discharge) Protein and fluid leak into nasopharyngeal interstitium ↑ Capillary permeability Protein and fluid leak into the bronchiole interstitium, accumulating around airway walls Airway wall becomes thickened, more readily apparent on x-ray Peribronchial cuffing (X-ray finding: bronchi appear like thickened ‘cuffs’ when viewed head-on) Inflammation stimulates the upregulation of mucous secreting goblet cells ↑ mucous production Mucous within alveoli ↑ intra- alveolar surface tensionà collapsing alveolar walls During inspiration, air enters the collapsed alveoli if airway is not yet occluded ↑ intra-alveolar pressure causes the alveoli to suddenly pop open Inspiratory crackles on auscultation Syncytia slough off the bronchial epithelium into airways Airways become narrower and occlude Disruption of the ciliated epithelial cells (which transport mucous out of the airways and into the pharynx, to be swallowed or evacuated) ↓ mucous clearance from airways Excess airway mucous triggers cough reflex Cough Interstitial edema Nasal Congestion Air is absorbed distal to occlusion (gas trapping) When all air is absorbed, alveoli collapse (resorptive atelectasis) ↓ gas exchange between blood and air in remaining alveoli ↓ O2 saturation & ↑ CO2 content of blood Narrower airways, especially during expiration, causes audible turbulent airflow Wheeze on auscultation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published November 29, 2020 on www.thecalgaryguide.com

Potassium-Sparing-Diuretics-Mechanism-of-Action-and-Side-Effects

Potassium-Sparing Diuretics: Mechanism of Action and Side Effects Potassium-Sparing Diuretics Authors: Samin Dolatabadi, Yan Yu* Reviewers: Jessica Krahn, Timothy Fu, Juliya Hemmett* * MD at time of publication Epithelium Sodium Channel Blockers (Amiloride and Triamterene) Inhibit Na+ channels (involved in Na+ reabsorption) in the luminal membrane of the principal cells in the cortical collecting duct Aldosterone Antagonists (Spironolactone and Eplerenone) Competitively blocks mineralocorticoid receptors and ↓ aldosterone effect in the renal tubules and throughout the body ↓ aldosterone effectà↓ expression of basolateral Na+/K+ pumps & luminal epithelium Na+ channels on the principal cells of cortical collecting duct Spironolactone’s molecular structure is similar to that of steroid hormonesàspironolactone can also block androgen receptors Anti-androgenic effects (due to ↓ androgen function in reproductive organs, skin, and on brain centers) Triamterene can form triamterene crystals and granular casts (unclear mechanism) ↓ Na+ reabsorption by principal cells ↓ in serum Na+ concentration: Hyponatremia ↓ K+ pumped out into the tubule by principal cells Crystals & casts obstruct tubular lumen → inflammation (unclear mechanism) Triamterene crystals are directly cytotoxic to tubular cells Only ~2-5% of Na+ filtered by the glomerulus is normally reabsorbed in the cortical collecting ductàthe ↑ in Na+ retained in cortical collecting duct is mild Water follows Na+ to maintain a balanced osmotic pressureà↑ in water in cortical collecting duct available for excretion ↑ positive charges in lumen relative to surroundings generates an electropositive tubular lumen Unfavorable electrical gradient ↓ secretion of positive charged ions into electropositive lumen ↓ libido Menstrual abnormalities (in women) ↓ acne Gynecomastia (in men) ↓ secretion of K+ ↑ in serum K+ concentration: Hyperkalemia Cardiac Arrythmias (See relevant slide on Hyperkalemia: Clinical Findings) Interstitial inflammation and tubular injury Drug-induced Nephrotoxicity Mild Diuresis ↓ blood volume ↓ Blood pressure/ Hypotension ↓ secretion of H+ ↑ in serum H+ concentration: Metabolic Acidosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 15, 2021 on www.thecalgaryguide.com

AAA-Pathogenesis

Abdominal Aortic Aneurysm (AAA): Pathogenesis Different parts of the aorta have different embryologic origins Atherosclerosis Hypertension Age > 65 Progressive deterioration of aorta structural integrity over life span Connective Tissue Disease Structurally abnormal protein or protein organization in aorta Autoimmunity Infection (e.g Chlamydia, Mycoplasma pneumoniae, Helicobacter pylori, human cytomegalovirus, herpes simplex virus) Antigens (substance that causes immune response) on virus or bacteria resemble local proteins in abdominal aorta Antibodies produced in response to infection inappropriately target host cells in the aorta Antibodies tag cells in the abdominal aorta for destruction by T-lymphocytes Immune-mediated destruction of aorta Smoking Genetics Unclear mechanisms Subacute (not clinically detectable) inflammation of aortic tissue Inflammatory cytokines are released and immune cells are recruited ↑ pressure on aorta and other vessel walls Infiltration of vessel wall by lymphocytes and macrophages Production of enzymes that break down elastin & collagen proteins (which provide most tensile strength to aorta) Aorta susceptible to damage Degradation of aortic connective tissue Biomechanical stress on vessels Authors: Olivia Genereux Davis Maclean Reviewers: Jason Waechter* Amy Bromley* Yan Yu* *MD at time of publication The exact mechanisms are complex, debatable, and an area of intensive research – the 3 mechanisms and associated pathophysiology presented here are generally thought to be the main causes of abdominal aortic aneurysms Infrarenal aorta has poorly developed vaso vasorum (dedicated blood supply to vessel wall) Infrarenal aorta relies solely on nutrient diffusion from aortic blood that crosses abdominal aorta Infrarenal aortic wall has fewer “lamellar” units (fibromuscular units) than other regions of the aorta Infrarenal aorta is less elastic & less able to distribute stress Loss of smooth muscle cells & thinning of tunica media Destruction of elastin in tunica media Normal layers of the aortic wall ↓ aortic tensile strength (ability to withstand stretching) Aorta expands and dilates due to internal pressure Tunica Intima (inner-most tissue layer of aorta) Tunica Media (layers of elastic tissue (elastin) and muscle fibers) Adventitia (thin outermost collagenous layer) (longitudinal section) Aortic aneurysms are usually infrarenal (85%) Abdominal Aortic Aneurysm Infrarenal aorta more prone to ischemia and has impaired repair potential Abnormal, irreversible dilation of a focal area of abdominal aorta (area of aorta between diaphragm & aortic bifurcation) to twice the diameter of adjacent normal artery segment Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published February 27, 2021 on www.thecalgaryguide.com

Cubital-Tunnel-Syndrome-Ulnar-Neuropathy

Cubital Tunnel Syndrome (Ulnar Neuropathy): Pathogenesis and clinical findings Osteoarthritis Rheumatoid arthritis Diabetes mellitus (see Calgary Guide slide on Diabetic Neuropathy) Degenerative bone & joint changes Autoimmune damage to joints Abnormal bone structure/lesions Idiopathic Hyperglycemia causes nerve damage (complex mechanisms) Elbow trauma Repetitive elbow flexion Authors: Chris Oleynick Alexandros Mouratidis Yan Yu* Reviewers: Annalise Abbott Sean Crooks Davis Maclean Hannah Koury Jeremy LaMothe* Ian Auld* * MD at time of publication Inflammation or edema in cubital tunnel (space between medial epicondyle of humerus and olecranon of ulna) where ulnar nerve is found ↓ size of the cubital tunnelà↑ pressure on internal contents (e.g. ulnar nerve) Axonal conduction is interrupted Myelin sheath is damaged ↓ blood supply to nerve Weakness of adductor pollicus longus (works to adduct thumb) ↑ compensatory activity of flexor pollicis longus with pinching ↓ activity of hypothenar muscles (which move the 5th digit) ↓ activity of 5th digit palmar interosseus muscles (which adduct the 5th digit) Cubital Tunnel syndrome: compression neuropathy Paresthesia Abnormal sensations of skin (“pins & needles”, tingling, burning, and/or numbness) in ulnar nerve sensory distribution ulnar nerve ↓ activity of muscles innervated by ulnar nerve (medial forearm flexors, hypothenar muscles, interossei muscles, adductor pollicis longus) + Tinel sign over cubital tunnel (tapping at medial elbow causes discomfort and/or paresthesia) Weak pinch & ↓ grip strength + Froment’s sign (thumb hyperflexion compensates for weak pinch) Hypothenar atrophy + Wartenburg’s sign (involuntary, excess abduction of 5th digit) of the Altered sensation in areas innervated by ulnar nerve (medial forearm and wrist, 5th digit, and medial half of 4th digit) + elbow flexion test (flexing elbow & extending wrist further ↓ volume of the cubital tunnelà paresthesia in ulnar nerve sensory distribution Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published January 12, 2017, re-published February 28, 2021 on www.thecalgaryguide.com

Achilles-Tendon-Rupture

Achilles Tendon Rupture: Pathogenesis and Clinical Findings Achilles tendon ruptures are multifactorial, and may arise from any one or combination of the factors below Authors: Alyssa Federico, Joseph Kendal Reviewers: Davis Maclean, Hannah Koury , Amanda Eslinger, Maninder Longowal, Dave Nicholl, Mehul Gupta, Gerhard Kiefer*, Yan Yu*, Jeremy LaMothe* * MD at time of publication Aging Iatrogenic factors E.g. use of fluoroquinolone antibiotics,or local or systemic corticosteroids Exact mechanisms remain unclear Exercise related factors Vascular compromise Any process that impairs blood flow to the Achilles tendon (e.g. peripheral artery disease) Impaired ability to heal from microtrauma Mechanical factors Abnormal biomechanics: bowleg, flatfoot, excessive supination, obesity, change in terrain Participation in vigorous exercise Excessive heat generation (hyperthermia) in Achilles tendon induces changes in the extracellular matrix Intra-tendinous collagen degeneration, disorientation, and thinningàcompromised Achilles tendon integrity Sudden shear stress and high tension in an already weakened Achilles tendon, stretching it beyond its capacity Haglund’s deformity: enlargement of the calcaneal postero- superior tuberosity Bony enlargement rubs on soft tissue and causes inflammation of Achilles tendon ↓ tendon strength from changes in extracellular matrix Episodic participation or sudden ↑ in exercise Irregular use renders Achilles tendon weaker Microtrauma to the and less flexible Achilles tendon on Achilles Tendon Abnormal loading Sudden, forced dorsiflexion of foot Eccentric contraction of the gastrocnemius-soleus complex The gastrocnemius muscle normally attaches to Achilles tendon to control plantar flexion of the foot With the Achilles tendon ruptured, contraction of the gastrocnemius muscle cannot induce plantar flexion Achilles tendon rupture Achilles tendon innervated by the sural nerve and tibial nerve Pain over rupture site (e.g. “like being kicked in the back of the leg”) Antalgic gate: abnormal gait developed to avoid pain while walking High tension at the origin and insertion points of the tendon causes the ends of the tear to separate The Achilles tendon contains blood vessels. Rupturing the tendon also ruptures the blood vessels withinàblood leaks out into tendon rupture site Bruising and swelling over rupture site ↓ resting ankle plantar flexion (Observed in prone position with knees flexed at 90 degrees) Passive contraction (e.g. squeezing) of the gastrocnemius does not cause plantar flexion + Thompson (calf squeeze) test Weak ankle plantar flexion Lack of push-off in gait Audible “pop” at time of injury Palpable gap between rupture ends Difficulty ambulating ↓ muscle use over time Calf atrophy Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published March 21, 2021 on www.thecalgaryguide.com

Thyroïdite

Thyroïdite : Pathogénie et résultats cliniques Authors: Jaye Platnich Reviewers: Matthew Harding Mark Elliott Hanan Bassyouni* * MD at time of publication Hypertrophie ferme et diffuse de la glande thyroïde (douloureuse dans le cadre d'étiologies subaiguë, radique et infectieuse) Symptômes généraux de l’hyperthyroïdie Post-natal Médicaments/ Radiation Thyroïdite bactérienne Subaigüe (post-virale) Abbréviations: • TSH- Hormone stimulant de la thyroïde Inflammation de la glande thyroïde Plusieurs méchanismes Brianna Ghali Sylvain Coderre* Phillippe Couillard* Translator: Infiltration de la glande thyroïde avec des globules blancs Destruction immunitaire de la glande thyroïde ↑ libération de T4 et T3 stockés par glande thyroïde endommagée durant 2-6 semaines (phase hyperthyroïde) ↓ sécrétion de T4 et T3 de la glande thyroïde endommagée durant des semaines-mois (phase hypothyroïde) Souvent une résolution à un état euthyroïde (normal), mais peut aussi rester dans un état hypothyroïde ↑ T4/T3 inhibe la libération de la TSH par la ↓ sécrétion TSH Réaction inflammatoire altère la fonction folliculaire normale (production T4/T3 et importation d’iode) glande pituitaire ↓ Absorption de l'iode par la glande thyroïde ↓ Capture de l'iode radioactif à la scintigraphie de médecine nucléaire Plusieurs méchanismes Symptômes généraux de l’hypothyroïdie ↓ T4/T3 stimule la liberation de la TSH par la ↑ sécrétion TSH Dommage altère la fonction folliculaire normale, (production T4/T3 et importation d’iode) glande pituitaire ↓ Absorption de l'iode par la glande thyroïde ↓ Capture de l'iode radioactif à la scintigraphie de médecine nucléaire Légende: Pathophysiologie Méchanisme Signes/Symptômes/Résultats labo Complications Publié June 19, 2013 on www.thecalgaryguide.com

Fat-Embolism-Syndrome

Fat Embolism Syndrome: Pathogenesis and clinical findings Panniculitis (conditions causing inflammation of subcutaneous fat) Non-trauma related (rare) Long bone fracture Pelvic fracture Orthopedic Trauma Intraosseous access Soft tissue injuries Chest compressions Bone marrow transplant Pancreatitis Diabetes mellitus Fat from bone marrow is disrupted and leaks into bloodstream via damaged blood vessels Fat globules obstruct dermal capillaries Capillaries rupture Blood leaks into the skin Petechial rash Non-Orthopedic Trauma (less common) Fat from injured adipose tissue is released from adipocytes into bloodstream Metabolic disturbance mobilizes stored fat and moves it into circulation Fat Embolism Syndrome the presence of fat globules in circulation Fat globules damage blood vessel walls Platelets stick to damaged areas Platelet aggregation ↑ circulating free fatty acids ↑ inflammatory cytokines (TNF, IL1, IL6) ↑ serum C Reactive Protein (an acute phase reactant) C reactive protein binds to lipid vesicles in circulation ↑ formation of lipid complexes in the blood Obstruction of cerebral vasculature ↓ blood flow and oxygen delivery to brain tissue Neurological findings: ranging from ↓ level of consciousness to seizures Notes: Large quantities of fat globules can obstruct pulmonary vasculature Blood clots form throughout the body Disseminated intravascular coagulopathy Back up of blood into right heart àRight ventricular dysfunction ↓ pulmonary arterial blood flow à↓ gas exchange in the lungs Higher CO2 & lower O2 levels in blood àdetected by chemoreceptors Chemoreceptors stimulate respiratory centre in the brain to ↑ rate of respiration Dyspnea / Tachypnea Authors: Tabitha Hawes Reviewers: Hannah Koury, Alyssa Federico, Davis MacLean, Mehul Gupta, Yan Yu*, Jeremy Lamothe* * MD at time of publication • Underlined findings indicate classic triad of symptoms (petechial rash, neurologic findings, dyspnea/tachypnea) • Clinical presentation of fat embolism syndrome is variable and may present with any or all of these findings ↓ pumping of blood into systemic circulation Hypotension Obstructive shock Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 19, 2021 on www.thecalgaryguide.com

Dry-Eye-Syndrome-Clinical-Findings

Dry Eye Syndrome (Keratoconjunctivitis sicca): Clinical Findings If dry eye is chronic or severe (e.g Sjögren’s syndrome) corneal ulcerations or scarring may occur Impaired visual acuity/ Blindness (does not improve with lubrication) See Calgary Guide: “Dry Eye Syndrome (Keratoconjunctivitis sicca): Pathogenesis” for explanation of etiology and pathogenesis Dry Eye Syndrome (Keratoconjunctivitis sicca): Disease of the ocular surface and tears characterized by loss of tear film homeostasis, tear film hyperosmolality and inflammation Tear film instability & hyperosmolarity Ocular surface inflammation: Immune cell (specifically T-Cell) destruction of corneal and conjunctival epithelium ↓ quantity and/or quality of tear film Inflammatory factors vasodilate conjunctival vessels, making the eye look redder in appearance Conjunctival injection Red eye Corneal surface irregularities Light rays pass through disrupted tear film and ocular surface structures as they enter the eye Degraded image quality as light passes through the eye Impaired visual acuity (improves with lubrication) ↓ lubrication over the eye surface ↑ friction on the eye during blinking or when opening eyes after sleep May cause corneal abrasion (See Calgary Guide: Corneal Abrasion) ↑ stimulation of corneal and conjunctival nerve endings Irritation and damage to corneal and conjunctival cells ↑ stimulation of nerve endings Chronic inflammation surrounding corneal nerves in conjunctiva and epithelium can lead to decreased neuronal firing thresholds (Neurosensory dysfunction / hyperalgesia) ↑ activity of the afferent portion of corneal reflex arc (responsible for reflex tearing: tearing in response to irritation of the eye) Foreign body sensation (scratching / feeling as if a foreign body, like a grain of sand, is in the eye) Minor (typically non-painful stimuli) may cause pain due to hypersensitive corneal nerves Corneal neuropathic pain (pain not fully explained by ocular surface changes, often resistant to standard treatments, sometimes still present following ocular surface anaesthesia if central pathways affected) Pain with temperature change and wind exposure Exact mechanism unknown Photophobia Burning sensation Paradoxical reflex tearing (↑ tearing, which does not improve dry eye due to altered tear composition, poor surface coverage or overflow of temporary tearing out of the eye Authors: Michael Penny, O.D. Davis Maclean Yan Yu* Reviewers: Natalie Arnold Saleel Jivraj, O.D. Adam Muzychuk* Victor Penner* *MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 6. 2021 on www.thecalgaryguide.com

COPD Acute Exacerbations

COPD Acute Exacerbations: Triggers and Signs/Symptoms Authors: Brianne McDonald, Yan Yu* Reviewers: Nilani Sritharan, Sean Doherty, Zihong Xie (谢梓泓), Zesheng Ye (叶泽生), Yonglin Mai (麦泳琳)*, Kerri Johannson* * MD at time of publication Notes: • The triggers for acute exacerbations of COPD are unknown in approximately 1/3 of cases • Changes in pulmonary function (e.g. FEV1) are poorly sensitive in the individual diagnosis of acute exacerbations of COPD due to individual variability Acute Bacterial Infection Activation of proinflammatory cytokines and recruitment of neutrophils Acute Viral Infection Epithelial cell secretion of cytokines and ↑ airway lymphocythemia Acute ↑ in airway inflammation (accumulation of inflammatory cells and release of harmful mediators, such as reactive oxygen species and proteases, into the lung tissue/airways) Air pollution (including cigarette smoke) ↑ reactive oxygen species in lungs Airway inflammation ↑ secretions that accumulate in the airway lumen Airway wall edema Limits outflow of air from lungs on expiration Airway bronchoconstriction in response to inflammation Constricted airways create audible turbulent airflow on expiration Systemic spread of inflammatory markers via the bloodstream cause inflammation throughout the body ↑ Cardiac Morbidity ↑ CRP Worsening of respiratory symptoms Irritation of cough reflexes in airways Cough ↑ Sputum production and sputum purulence ↑ Wheeze Unexpired air becomes trapped in the lungsàDynamic Hyperinflation Bloodflow to lungs continue to perfuse under- ventilated regions of lungs àV/Q Mismatch Lungs are larger àmore blood remains in lungs à↓ preload Acute Respiratory Failure Tachypnea ↑ Dyspnea Accessory Muscle Use Attempts to restore normal arterial CO2 and O2 levels Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 21, 2019, updated October 6, 2021 on www.thecalgaryguide.com

Hypercortisolemia

Hypercortisolemia (Cushing’s Syndrome): Clinical Findings Cortisol is a net catabolic hormone affecting many body systems, serving to release energy into the blood in response to stress. Excess cortisol also impacts circulation and impairs immune function. Excess Serum Cortisol affects: Authors: Samin Dolatabadi, Yan Yu* Reviewers: Meena Assad, Amanda Henderson, Brooke Fallis, David Campbell* * MD at time of publication Bone and Calcium Metabolism Kidney and vasculature Excess cortisol in the renal tubule saturates the enzyme 11β- HSD2, which converts cortisol to cortisone Capacity of body to convert cortisol to cortisone is exceeded Excess cortisol can mimic aldosterone and bind to mineralocorticoid receptors (cortisone can’t bind to these receptors) ↑ Aldosterone effect → ↑ Na+ reabsorption from the cortical collecting duct into blood vessels Liver and Peripheral Tissue Cortisol ↑ gluco- neogenesis in liver, and ↑ insulin resistance by body tissue (unclear mechanisms) Hyper- glycemia Reproductive System Cortisol exerts negative feedback on hypothalamus à↓ gonadotropin releasing hormone (GnRH) secretion ↓ GnRH → ↓ LH/FSH → ↓ estrogen and testosterone production (especially important in females) Infertility, ↓ Libido, Irregular Menses Adipose Tissue Cortisol ↑ fat breakdown (lipolysis) Selective expression of cortisol receptor on different adipose tissuesàcentral, facial, dorsal fat is less broken down than in other areas (mechanism unclear) Combined with cortisol ↑ appetite: Skin & Connective Tissue ↑ Serum cortisol à↓ Fibroblast proliferation → ↓ Collagen synthesis Skin atrophy with loss of connective tissue Muscle ↑ Proteolysis & ↓ Protein synthesisà↓ muscle growth and function Immune System Normal serum cortisol protects against damaging effects of uncontrolled inflammatory and immune responses ↑ Serum cortisolà over-suppression of inflammation and impaired cell- mediated immunity ↑ Serum cortisol leads to ↓ Intestinal Ca2+ absorption and ↓ renal Ca2+ reabsorption ↓ Serum Ca2+ ↑ PTH secretion ↑ Serum cortisolà↑ RANKL:OPG ratio ↓ Osteoblast activity & ↑ Osteoclast activity Cardiac muscle Cardio- myopathy, Heart Failure Skeletal muscle, especially upper arms & thighs (for unclear reasons) Proximal Muscle Weakness Easy Bruising ↑ abdominal size stretches the fragile skin to become thinneràvenous blood of the underlying dermis becomes visible Purple Striae If hypertension is chronic Ca2+ resorption from bone into the blood Osteoporosis Supraclavicular & Dorsal Fat Pads Central Obesity Poor Wound Healing Susceptibility to infection Round Face (Moon Face) Abbreviations: • RANKL – Receptor activator of nuclear factor kappa-Β ligand • OPG – Osteoprotegerin • 11β-HSD2 – 11β-hydroxysteroid dehydrogenase type 2 Water follows Na+ into blood vessels to balance the osmotic pressure between the blood and renal tubules Water reabsorption → Expansion of blood volume Hypertension Both primary Cushing’s (e.g. adenomas that extend into zona reticularis of the adrenal cortex) and central/secondary Cushing’s (e.g. ↑ ACTH stimulation of zona reticularis) are associated with ↑ adrenal androgen secretion Removal of positively charged Na+ from tubular lumen creates a negative luminal environment K+ follows the electrical gradient and is secreted into tubular lumen ↓ Serum K+ concentration Hypokalemia Arrhythmia, Paralysis, Cramps (see Hypokalemia: Clinical Findings slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 17, 2021 on www.thecalgaryguide.com Hirsutism, Acne

Acne Vulgaris Complications

Acne vulgaris: Complications Acne vulgaris Cutaneous inflammation caused by acne lesions True Scars Authors: Stephen Williams Reviewers: Mehul Gupta, Lauren Lee, Yan Yu*, Laurie Parsons* * MD at time of publication Elevated Acne Scars ↑ collagen exceeds collagen degradation Prostaglandins (PGE2), leukotrienes (LTC4, LTD4), and thromboxane A2 are released in response to inflammation Atrophic Acne Scars Collagen degradation and disordered deposition during healing Formation of round- rectangular depressions with defined edges Box Car Scar True scars with textural change, very slow autoresolution over time The pigmentary changes and true scar formation resulting from acne may be more psychologically distressing than the original acne lesions Healing processes favoring deposition of Type 1 & Type 3 collagen Proliferation beyond the borders of original acne lesion Keloid Formation Healing processes favoring deposition of Type 4 collagen Growth remains within the margins of acne lesion Hypertrophic Scar Formation Dermal inflammation: Due to disruption of basal cell layer, melanin released and trapped by macrophages in the dermis. Epidermal inflammation: ↑ melanin production and transfer of melanin to keratinocytes Microvascular dilatation and ↑presence of erythrocytes Erythematous macules appear where acne was present Post- inflammatory Erythema (PIE). More common in Fitzpatrick Skin Types I-III Formation of V- shaped tracts with sharp margins Ice Pick Scar Formation of a shallow edged depression layer anchored to dermal layer and subcutis Rolling Scar Pigmented macules or patches appear where acne was present Post-inflammatory Hyperpigmentation (PIH). More common in Fitzpatrick Skin Types III-VI No textural change, slow autoresolution over time True scars with textural change, do not resolve over time Psychosocial Concerns (Depression, Anxiety, Social Isolation) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 19, 2021 on www.thecalgaryguide.com

Vestibular Neuritis

Vestibular Neuritis: Pathogenesis and Clinical Findings Authors: Ryan Chan Jonathan Wong Reviewers: Mehul Gupta Davis Maclean Saud Sunba Yan Yu* Euna Hwang* * MD at time of publication Recent viral illness or upper respiratory tract infection Virus spreads along upper respiratory mucosa and into the inner ear structures Vestibular Neuritis Presumed idiopathic viral-induced inflammation of the vestibular nerve; typically unilateral Reactivation of Herpes Simplex Virus-1 in vestibular (Scarpa’s) ganglion Inflammatory cell infiltration leads to degeneration and atrophy of the vestibular nerve Superior Vestibular Neuritis (40-48%) Inflammatory cells traverse through only one long bony canal, easier for inflammatory cell infiltration Loss of afferent innervation from the superior and horizontal semicircular canal (SCC), utricle, and parts of the saccule Combined Superior Vestibular Neuritis and Inferior Vestibular Neuritis (34-56%) Inferior Vestibular Neuritis (1.3-18%) Inflammatory cells must pass through two separate bony canals, making inflammatory cell infiltration more difficult Loss of afferent innervation from the posterior semicircular canal (SCC) and saccule Utricular degeneration Displacement of otoliths/ otoconia (commonly into the posterior SCC) BPPV (can occur several months after onset of neuritis) Loss of horizontal SCC afferent neuron signaling to the brain Unilateral Loss or ↓ of normal nystagmus response to Caloric Testing (insertion of cold and warm water/air into the ear canal while supine) Loss of utricular afferent neuron signaling to the brain ↓ or absent Ocular Vestibular- Evoked Myogenic Potentials (VEMPs) and Normal Cervical VEMPs ↓ unilateral vestibular input to the brain leads to acute phase symptoms (over time, brain can compensate which allows for some symptom improvement) Loss of posterior SCC and saccular afferent neuron signaling to the brain ↓ or absent Cervical VEMPs, but Ocular VEMPs are normal ↓ or absent input to the ipsilateral vestibular nuclei elicits a vestibular nucleus response similar to contralateral SCC excitation Acute-Phase Spontaneous Nystagmus Fast phase beats away from the affected side (3- 10 days) And Loss of ocular fixation on Head Impulse Test ↓ or absent saccular input to the lateral vestibular nuclei (e.g., lateral vestibulospinal tract) results in the loss of lower limb postural adjustability Postural Instability (e.g., abnormal Romberg/sharpened Romberg, Fukuda step test) Bilateral mismatch of vestibular information to the brain Peripheral Vertigo (lasts several hours to days; rapid onset, severe, constant) Nausea and Vomiting Only the vestibular part of the vestibulo- cochlear nerve is affected, not the cochlear nerve No Hearing Loss or Tinnitus Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 19, 2021 on www.thecalgaryguide.com

COPD-发病机制

COPD: 发病机制 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: ! 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " title="COPD: 发病机制 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 慢性阻塞性肺疾病 (COPD) 如果出现在气道周围 气流阻塞 肺不能完全排空 气体，气体潴留 于肺泡(肺过度 充气) 总呼气时长大于 正常时长 呼气相延长 肺组织损伤 呼气时，将空气排出肺外 的弹性回缩力↓ 肺不能完全排空气体， 气体潴留于肺泡内 (肺过度充气) 肺容积↑，膈肌紧张 性收缩(膈肌平坦) 呼气时，胸膜腔正压挤压气道 à 气道阻塞↑ 肺泡通气↓ 血液氧合↓ (低 氧血症) 身体组织灌注 量↓ (比如脑、 肌肉) 疲劳; 运动耐量↓ 黏液生成↑ 清除黏液的上皮纤 毛细胞数量↓ (受 气道炎症损伤) 慢性咳嗽伴咳 痰 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 容积较大 的肺需要 更加努力 才能通气 呼吸肌必须 更用力才能 呼吸 听诊闻及狭窄气 道中的湍流气流 呼气喘鸣音 呼吸困难 气促，尤其是劳累 膈肌无法进一步收缩以 产生深呼吸 呼吸浅快 为了呼吸， 胸壁必须延 展得更大 桶状胸 晚期病人: 患者试图在较高的口 慢性疲劳导致 患者动用辅助呼吸肌和膈肌呼吸， 腔内气压下进行呼气， 活动耐量下降 从而使气道更开放 以改善气流 晚期病人:膈肌 “平坦” ，持续吸气进一步压 缩膈肌à 向内拉季肋部胸壁 胡佛征 (吸气时，胸廓下侧季肋部内收) 缩唇呼吸 肌肉无力 & 消瘦 端坐呼吸 (调动胸肌) 颈部肌肉收 缩(胸锁乳 突肌、斜角 肌) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Findings on Investigations Chronic Obstructive Pulmonary Disease (COPD) Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication Airflow obstruction Lung tissue damage ↓ ventilation of alveoli Blood perfusing ill- ventilated alveoli does not receive normal amounts of oxygen During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction) No elastic recoil to push air out of lungs Loss of lung parenchyma and vasculature ↓ surface area for gas exchange ↓ diffusion capacity (on spirometry) Hypoxemia: PaO2 < 70mmHg (on ABGs) Abbreviations: • FEV1: Forced expiratory volume in 1 second • FVC: Forced vital capacity • TLC: Total lung capacity • VC: Vital Capacity Investigations for COPD : • Spirometry (Pulmonary function test) Total expiration time takes longer than normal FEV1/FEV < 0.7 (on spirometry) Lungs don’t fully empty More air trapped within lungs (hyperinflation) More CO2 remains and diffuses into the blood Hypercapnia: PaCO2 > 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " />

COPD-临床表现

COPD: 临床表现 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: ! 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " title="COPD: 临床表现 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 慢性阻塞性肺疾病 (COPD) 如果出现在气道周围 气流阻塞 肺不能完全排空 气体，气体潴留 于肺泡(肺过度 充气) 总呼气时长大于 正常时长 呼气相延长 肺组织损伤 呼气时，将空气排出肺外 的弹性回缩力↓ 肺不能完全排空气体， 气体潴留于肺泡内 (肺过度充气) 肺容积↑，膈肌紧张 性收缩(膈肌平坦) 呼气时，胸膜腔正压挤压气道 à 气道阻塞↑ 肺泡通气↓ 血液氧合↓ (低 氧血症) 身体组织灌注 量↓ (比如脑、 肌肉) 疲劳; 运动耐量↓ 黏液生成↑ 清除黏液的上皮纤 毛细胞数量↓ (受 气道炎症损伤) 慢性咳嗽伴咳 痰 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 容积较大 的肺需要 更加努力 才能通气 呼吸肌必须 更用力才能 呼吸 听诊闻及狭窄气 道中的湍流气流 呼气喘鸣音 呼吸困难 气促，尤其是劳累 膈肌无法进一步收缩以 产生深呼吸 呼吸浅快 为了呼吸， 胸壁必须延 展得更大 桶状胸 晚期病人: 患者试图在较高的口 慢性疲劳导致 患者动用辅助呼吸肌和膈肌呼吸， 腔内气压下进行呼气， 活动耐量下降 从而使气道更开放 以改善气流 晚期病人:膈肌 “平坦” ，持续吸气进一步压 缩膈肌à 向内拉季肋部胸壁 胡佛征 (吸气时，胸廓下侧季肋部内收) 缩唇呼吸 肌肉无力 & 消瘦 端坐呼吸 (调动胸肌) 颈部肌肉收 缩(胸锁乳 突肌、斜角 肌) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Findings on Investigations Chronic Obstructive Pulmonary Disease (COPD) Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication Airflow obstruction Lung tissue damage ↓ ventilation of alveoli Blood perfusing ill- ventilated alveoli does not receive normal amounts of oxygen During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction) No elastic recoil to push air out of lungs Loss of lung parenchyma and vasculature ↓ surface area for gas exchange ↓ diffusion capacity (on spirometry) Hypoxemia: PaO2 < 70mmHg (on ABGs) Abbreviations: • FEV1: Forced expiratory volume in 1 second • FVC: Forced vital capacity • TLC: Total lung capacity • VC: Vital Capacity Investigations for COPD : • Spirometry (Pulmonary function test) Total expiration time takes longer than normal FEV1/FEV < 0.7 (on spirometry) Lungs don’t fully empty More air trapped within lungs (hyperinflation) More CO2 remains and diffuses into the blood Hypercapnia: PaCO2 > 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " />

Chronic Cough Pathogenesis_2021

Chronic Cough: Pathogenesis ACE Inhibitors Protussive mediator accumulation (bradykinin, substance P) Infection IP; likely chronic ↑ cough receptors commonly pertussis- related or post-viral Asthma ↑ EDN ↑ MBP levels in RT Neoplasm Bronchiectasis COPD GERD Allergic Rhinitis ↑ sputum production and accumulation Damage from chronic inflammation causes poor mucus clearance Inhalants trigger ↑ cytokines ↑ mucus Aspiration of refluxed microdroplets Irritation by post- nasal drip ↑ inflammatory mediators in RT Mechanical obstructions (i.e. mediastinal masses, neoplasms) Foreign body Presence irritation of irritants Stimulation of sensory nerve receptors expressed on nerve endings penetrating the epithelia of the upper RT Abbreviations: • RT: respiratory tract • IP: indefinite pathophysiology • GERD: Gastro-esophageal reflux disease • EDN: Eosinophil-derived neurotoxin • MBP: Major basic protein • COPD: Chronic Obstructive Pulmonary Disease Complications: Syncope, insomnia, hemoptysis, rib fractures Slowly adapting receptors Respond to mechanical forces during breathing Stimulation of the vagus nerve Activation of nucleus tractus solitarius in central respiratory generator (brainstem) Generation of efferent cough signal Chronic cough: Cough of over 8 weeks duration with no dyspnea or fever C-fibre receptors Respond to chemical stimuli (bradykinin, capsaicin, acid/alkaline solutions, mannitol, hypertonic saline, and other inhaled irritants) Authors: Arsalan Ahmad Lance Bartel Reviewers: Midas (Kening) Kang Usama Malik Ciara Hanly Yonglin Mai (麦泳琳) Yan Yu*, Eric Leung* * MD at time of publication Rapidly adapting receptors Responds to mechanical stimuli, such as physical obstruction of the airways Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 06, 2018, updated Dec 4, 2021 on www.thecalgaryguide.com

hip-osteoarthritis-pathogenesis-and-clinical-findings

Hip Osteoarthritis: Pathogenesis and clinical findings Authors: Ebrahim Alawadhi, Alyssa Federico Reviewers: Mehul Gupta, Tara Shannon, Yan Yu*, Richard Ng* * MD at time of publication Primary causes Aging ↓ Synovial fluid in the hip joint Secondary causes Gender Females > males Genetics Family history of osteoarthritis High-impact sports, activities, and occupations Repetitive stress on the hip joints Obesity ↑ Loading on hip joints Inflammatory disease (e.g. Rheumatoid arthritis ) Trauma Infection (e.g. septic arthritis) Anatomical abnormality (e.g. developmental hip dysplasia) ↑ Cartilage stiffness and degeneration ↑ Friction in the hip joint with movement Changes in normal hip architecture Abnormal load on the hip joint Radiographic changes See Osteoarthritis (OA): X-Ray Features slide Repeated attempts to repair cartilage damage and bone Bone spur (bony growth) formation in joint Joint fluid accumulation from mild inflammation of the joint Stiffness Limited joint movement Hip Osteoarthritis Multifactorial condition that manifests as degeneration of cartilage, bone, and synovium in the hip joint ↓ Cartilage between femoral head and acetabulum ↑ Bone on bone contact Mechanical symptoms (crepitus, locking, clicking, catching) Bones rubbing together activates nociceptors within the hip joint Nociceptors further aggravated by actions that ↑ bone on bone contact (e.g. prolonged loading, movements that ↓ joint space) Worsening pain in the groin region Favour the affected leg to avoid pain while walking ↓ Space for the femoral head to move ↓ Range of motion of affected hip joint Limited range of motion when walking Antalgic gait ↓ Use of muscles around the affected hip Muscular atrophy around the hip C Sign: patient identifies location of pain by cupping lateral hip with one hand, which creates a “C” shape with that hand Pain in groin region ↑ Sensitivity of surrounding nerves Radiating pain to buttocks and knee Inactivity Hip instability when walking Muscle contractures ↑ Falls Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 6, 2022 on www.thecalgaryguide.com

cough-physiology

Cough: Physiology Mass or particulate matter in the throat & airways ↑ pressure on mucosa Pressure on rapidly and slowly adapting mechanoreceptors Mechanoreceptor activation opens ion channels on vagus neurons Authors: Calvin Howard Reviewers: Nilani Sritharan Ciara Hanly Yonglin Mai (麦泳琳)* Yan Yu* Stephen Field* * MD at time of publication Systemic immune reaction Inflammation of alveoli Cytokine release Cytokines bind to sensory neurons Neurons ↑ receptor sensitivity and number ↑ sensation of stimuli Ionic flux across neuronal membrane Vagus neurons depolarize Thinly myelinated axons (Aδ fibers) General chemicals, heat, cold, and hydrogen ions Transient receptor potential vanilloid (TRPV)/Transient receptor potential ankyrin (TRPA) receptors activate TRPV/TRPA activation opens ion channels on vagus neurons Unmyelinated axons (C fibers) carry depolarization Vagus nerves conduct depolarization to carry depolarization SUMMARY Afferent pathways activated Cough center (medulla) Efferent pathways Respiratory muscles nucleus of the solitary tract Medullary nuclei activated, stimulates: Phrenic nerves Diaphragm contraction Spinal nerves External intercostal contraction Vagal nerves Glottis closure Spinal nerves Thoracic, abdominal, and pelvic muscle contraction Vagal nerves Glottis opens, allowing forceful expiration Intrathoracic pressure and volume decrease Volume in lungs increases Intrathoracic pressure increases Mechanical Cough Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 1, 2019, updated Dec 5, 2021 on www.thecalgaryguide.com

proximal-biceps-tendon-rupture

Proximal Biceps Tendon Rupture: Pathogenesis and clinical findings Author: Alyssa Federico Reviewers: Tara Shannon, Mehul Gupta, Yan Yu*, Gareth Ryan* * MD at time of publication Aging Decreased tendon strength from age- related changes in extracellular matrix Male gender Smoking Corticosteroid and fluoroquinolone use Shoulder Overuse Repetitive overhead sports like swimming & tennis Shoulder overuse injuries (rotator cuff tears, shoulder impingement, & tendonitis) place more stress on the proximal biceps tendon Repetitive microtrauma and inflammation of biceps tendon Compromised biceps tendon integrity from intra-tendinous collagen degeneration, disorientation, and thinning Increased involvement in physical labour and hobbies Impaired cell proliferation and healing after injury Exact mechanisms remain unclear Bicep tendon involved in shoulder stabilization, elbow flexion, and forearm supination Biceps muscle cannot contract with as much force when one head is detached Heavy lifting or fall on outstretched handà sudden tension in the proximal biceps tendon Proximal biceps tendon rupture Long head of proximal biceps tendon detaches from bony attachment on supraglenoid tubercle Audible “pop” at time of injury No tension to hold proximal bicep tendon head in place Proximal bicep tendon head retracts distally Biceps muscle fatigue and cramping Weakness in shoulder flexion, elbow flexion & supination Nerve damage (musculocutaneous nerve) during injury Local inflammatory response at site of injury Surrounding blood vessels damaged during injury Blood collection under skin surface Immediate bruising over rupture site Sudden and sharp pain at shoulder with initial injury Inflammatory response aggravates musculocutaneous nerve Swelling over rupture site + Speed test: affected elbow extended and forearm supinated. Shoulder flexed against resistanceàpain at bicipital groove + Neer test: on affected side, scapula stabilized while arm passively flexed and internally rotatedàpain at bicipital groove + Yergeson test: affected elbow flexed at 90° and forearm pronated. Forearm supinated against resistance àpain at bicipital groove “Popeye” deformity: mass in distal upper arm due to excessive retraction of biceps muscle distally, away from its origin Palpable gap between proximal biceps tendon and bicipital groove Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 20, 2022 on www.thecalgaryguide.com

distal-biceps-tendon-rupture

Distal Biceps Tendon Rupture: Pathogenesis and clinical findings Authors: Alyssa Federico Reviewers: Tara Shannon, Mehul Gupta, Yan Yu*, Gareth Ryan* * MD at time of publication Aging ↓ Tendon strength from age-related changes in extracellular matrix Male gender Overuse Common in throwing and racquet sports Repetitive microtrauma and inflammation of biceps tendon Corticosteroid and fluoroquinolone use Smoking Hypovascularity Area of hypovascularity between regions supplied by the brachial artery and posterior radial recurrent artery Impaired ability to heal from microtrauma Mechanical impingement Compression of distal biceps tendon by surrounding bone (radial tuberosity, proximal ulna) during forearm pronation Repetitive compressionà tendon degeneration ↑ Involvement in physical labour and hobbies Exact mechanisms remain unclear Impaired cell proliferation Biceps tendon inserts at the radial tuberosity to control forearm supination and flexion Compromised biceps tendon integrity from intra-tendinous collagen degeneration, disorientation, and thinning Sudden eccentric force to flexed elbow (forced lengthening of a contracted bicep muscle)àtension in the distal biceps tendon Biceps muscle cannot contract when distal tendon is detached from insertion site Distal biceps tendon rupture Complete detachment of distal biceps tendon at the attachment site on the radial tuberosity Audible “pop” at time of injury Weak forearm supination and flexion + Ruland biceps squeeze test: Affected elbow held in 60-80° of flexion, with forearm slightly pronated. Distal biceps muscle squeezed by practitioner à forearm does not supinate Local inflammatory response at site of injury Inflammatory response aggravates musculo- cutaneous nerve Pain over rupture site after initial injury Swelling over rupture site Nerve damage (musculocut aneous nerve) during injury Sudden and sharp pain at elbow at initial injury Surrounding blood vessels damaged during injury Blood collects under skin surface Immediate bruising over rupture site Biceps tendon retracts proximally High tension during tendon retraction Fragment of bone torn off from tendon insertion site on radial tuberosity Avulsion fracture of radial tuberosity Connective tissue attachment (aponeurosis) torn during injury Palpable gap between distal end of biceps tendon & radial tuberosity + Hook test: Elbow actively flexed to 90° and forearm supinated. Index finger of examiner cannot be placed beneath distal aspect of biceps tendon (>1 cm deep) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 20, 2022 on www.thecalgaryguide.com

abnormal-uterine-bleeding-aub-pathogenesis-and-clinical-findings

Abnormal Uterine Bleeding: Pathogenesis and clinical findings Authors: Joshua Yu, Karen Paik Reviewers: Ayaa Alkhaleefa, Parker Lieb, Hypothyroidism Hypothalamus senses ↓ serum thyroxine ↑Thyrotropin releasing hormone (TRH) release from hypothalamus ↑Prolactin (see Feedback Loop: Prolactin) Exogenous estrogen (e.g. estrogen-only birth control) ↑ Peripheral adipose tissue ↑ Aromatase (enzyme present in adipose tissue) ↑ Conversion of androgens to estrogens (aromatization) Excessive stress, exercise, low body mass (mechanism unclear) ↓ Hypothalamic gonadotropin releasing hormone secretion ↓Luteinizing hormone and follicle stimulating hormone release from pituitary ↑ Estrogen Heavier bleeding Angiogenesis in tumour tissue Polycystic ovarian syndrome (see slide) Pelvic inflammatory disease Immature hypothalamic- pituitary-ovarian axis (an immature axis is transient in most females) ↓ Positive feedback of estrogen in late follicular stage No LH surge Adenomyosis (endometrial tissue grows into uterus muscular wall) Endometrial polyps Retained products of contraception Infection Inflammation of endometrium Endometrium is more fragile Anovulatory Bleeding Leiomyoma (benign tumour in myometrium) Tara Shannon, Hannah Yaphe, Dr. Sarah Glaze* * MD at time of publication Ovarian Scarring Foreign bodies Intrauterine device perforation Physical trauma Impaired follicle maturation Anovulation Corpus luteum does not form No ovarian progesterone production ↑ Estrogen to progesterone ratio Proliferative effect of estrogen unopposed Endometrial proliferation No progesterone to organize growing endometrium Disorganized endometrium overgrows and sloughs off Irregular bleeding Menopause Premature ovarian insufficiency Intermittent congestion of polyp blood supply Transient ischemia and slight polyp necrosis Altered growth factor production Vascular dysregulation and leakier vessels Coagulopathies (e.g. von Willebrand disease) Impaired hemostasis Invasion of normal tissue ↓ Estrogen (hypoestrogenism) Atrophy of endometrium and vulvovaginal tissue Dry endometrial surfaces (↓ fluid to prevent friction) Endometrial carcinoma Micro- erosions of epithelium Inflammation Evidence unclear Heavier and more irregular bleeding Spotting Heavier and more irregular bleeding Light bleeding and spotting Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 2, 2022 on www.thecalgaryguide.com

rhumatisme-psoriasique-pathogenese-et-resultats-cliniques

rhumatisme-psoriasique-pathogenese-et-resultats-cliniques Psoriatic Arthritis: Pathogenesis and clinical findings Auteur: Payam Pournazari Rédacteurs: Yan Yu Scott Rapske Liam Martin* Traducteurs: Dianne Ganeswaran Stephen Williams Sylvain Coderre* * MD au moment de publication Note: L’arthrite rhumatoïde peut survenir avant ou après le psoriasis (la pathogenèse est la même). Augmentation de l’activité ostéoclastique Érosion de l’os sous- chondral mais formation de nouvelle osseuse ailleurs dans l’articulation Radiographie: la périostite; les syndesmophytes, érosions, déformation du crayon en godets (les articulations IP), ankylose des articulations IP HLA B27, Cw6 et d’autres sous- types Antécédents familiaux positifs Activation des cellules T (mécanisme inconnu) Infiltration du tissu synovial de l’articulation par les cellules T et B, cellules tueuses naturelles et les macrophages Production augmentée des molécules inflammatoires (les facteurs de nécrose tumorale [TNFs], les interleukines, etc.) qui agissent de façon systémique (dans tout le corps) Dans les tendons et le tissu conjonctif Inflammation des enthèses et du tissu conjonctif provoque le gonflement Dans la peau Réaction immunitaire détruisant les structures de la peau et des ongles (Voir diapositive Psoriasis) Le psoriasis en plaques sur la peau, dépressions punctiformes, onychorrhexie, taches d’huile, onycholyse, décoloration et hyperkératose Angiogenèse et vascularite dans les vaisseaux sanguins de la membrane synoviale Dans les articulations Les cytokines inflammatoires stimulent les nocicepteurs locaux 1. Oligoarthrites - asymétriques 2. Arthrite des articulations IPD 3. Polyarthrite rhumatoïde - symétrique 4. Atteinte axiale (raison inconnue, probablement en raison de « biomécanique », « innervation », et « vascularisation ». 5. Arthrite mutilante (grave et destructrice) L’enthésite (Douleur/sensibilité à l’insertion du ligament dans l’os) La dactylite (Inflammation de tout le doigt – les tissus mous et les articulations sont enflammés Légende: Physiopathologie Mécanisme Signe/Symptôme/Résultats de Laboratoire Complications Publié 10 November 2012 sur www.thecalgaryguide.com

acute-cholecystitis

Acute Cholecystitis: Pathogenesis and clinical findings Gallstone blocks the cystic duct, backing up bile into the gallbladder Gallstones causing physical trauma to gallbladder wall Irritation of adjacent diaphragm, stimulates phrenic nerve (C3-C5) Activates stretch receptors of visceral peritoneum, stimulates foregut autonomic nerves (T5-T8) Inflammatory mediator (i.e. prostaglandin) release by gallbladder and systemic inflammatory response Thickened gallbladder wall on ultrasound (gold standard test) On inspiration, the diaphragm pushes the gallbladder downward Irritation of parietal peritoneum, stimulates somatic nerves ↑ Permeability of vessels with systemic inflammation, which leak fluid from the blood into the interstitial space Radiating pain to the back and right shoulder Dull, diffuse abdominal pain referred to the epigastric region Fever, nausea/vomiting, tachycardia Positive Murphy’s sign (pain upon palpation of right upper quadrant [RUQ] on inspiration) Persistent RUQ pain, abdominal guarding and peritoneal signs Dehydration Authors: Yan Yu, Vina Fan Reviewers: Dean Percy, Mirna Matta, Crystal Liu, Ben Campbell Maitreyi Raman* * MD at time of publication Inflammation self-perpetuates Irritation of inner gallbladder wall/mucosa ↑ Gallbladder lumen pressure Intraluminal pressure exceeds arterial pressure ↓ Blood flow to gallbladder Gallbladder ischemia Local inflammation, loss of gallbladder mucosal integrity Bacterial invasionàtransmural inflammation of gallbladder Without treatment, prolonged ischemia and inflammation of the gallbladder Gallbladder gangrene (20%) Gallbladder perforation (20%) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 4 2019, updated May 16 2022 on www.thecalgaryguide.com

clostridium-difficile-infection-pathogenesis-and-clinical-findings

Clostridium difficile (C. diff) Infection Authors: Ryan Brenneis, Sravya Kakumanu Reviewers: Yoyo Chan, Sean Doherty, Vina Fan, Ben Campbell, Dr. Steve Vaughan*, Dr. Sylvain Coderre* * MD at time of publication Community exposure Infected close contacts Nosocomial exposure (most common) Poor hand hygiene and sanitization of surfaces and medical equipment Nosocomial risk factors Any antibiotic use (Especially clindamycin, fluoroquinolones, penicillins, cephalosporins) ↑ Antibiotic resistant strains Presence of pre-disposing risk factors (Note: do not need to be present for infection) Recent GI surgery Chemotherapy that has antimicrobial and immunosuppressive effects Usage of medications that reduce stomach acid (↑ pH) ↑ C. diff spores on surfaces and personnel Contact exposure Environmental exposure to C. diff carriers Inoculation of GI tract Disruption of normal gut microbiome allowing C. diff overgrowth Comorbidities (>65 years old, cirrhosis, inflammatory bowel disease, enteral feeding, obesity) via fecal-oral route Clostridium difficile Infection of GI Tract Spores unaffected by antibiotics germinate post-antibiotic treatment Infection recurrence Pseudomembranous colitis on endoscopy (colonic ulcerations potentially seen with severe infection) Hypotension Acute kidney injury Release of C. diff toxin A and B inactivates Rho and Ras GTPases in colonic epithelial cells (colonocytes) (Rho and Ras GTPases control cytoskeletal dynamics and gene expression) Cytoskeletal disorganization and arrest of RNA synthesis causes necrosis of colonocytes and triggers host immune response Neutrophil chemotaxis and activation ↑ Inflammation of colon Disruption of tight junctions between colonocytes Release of fluid into intestinal lumen and inability of colon to reabsorb it Toxic megacolon Bowel perforation Bloody stool (<10% of patients) Abdominal cramps Large bowel dilation from muscle paralysis Inflammation and destruction of underlying smooth muscle Breakdown of colonocyte cell membranes Inflammation of visceral peritoneum Volume depletion Watery diarrhea: ↑ frequency, small volume Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 30, 2019, updated May 16, 2022 on www.thecalgaryguide.com

constatations-classiques-de-sclerose-en-plaques-sep-sur-irm-cerebrale

Constatations classiques de sclérose en plaques (SEP) sur IRM cérébrale Auteurs: Evan Allarie Davis Maclean Viesha Ciura* Rédacteurs: Yan Yu* Traducteurs: Liana Martel Eddy Lang* * MD au moment de la publication Infiltrations dans la région infratentorielle Perte de la densité neuronale/axonale dans la région affectée, remplacée par une gliose au fil du temps Remarque : les constatations peuvent varier. Les constatations présentées ici ne sont pas exhaustives, mais constituent certaines des zones les plus fréquemment mises en évidence par l'IRM du cerveau dans la SEP. Les sites les plus communément observés sont : les régions juxtacorticales, périventriculaires, infratentorielles, la moelle épinière et le nerf optique. Cependant, les lésions peuvent apparaître partout où il y a de la myéline dans le SNC. L'inflammation et la destruction actives permettent au contraste de gadolinium de traverser la barrière hémato-encéphalique, ce qui peut être visualisé comme un marqueur de l'inflammation active dans la SEP Lésion classique du nerf optique (CN II) en cas de névrite optique. Rehaussement par Gadolinium (↑ intensité du signal de la lésion après l’injection de gadolinium) sur cette image en T1 démontre une inflammation active Image Credits: Dr. Viesha Ciura Pour plus de détails sur la pathogenèse, voir la diapositive du Guide de Calgary: Multiple Sclerosis (MS): Pathogenesis and Clinical Findings Inflammation dans le système nerveux central (SNC) Les cellules T, les cellules B et les macrophages infiltrent le SNC Infiltration se produit autour des veinsàinflammation locale Infiltrats périveineux autour des veines médullaires (perpendiculaires aux ventricules) Inflammation et destruction de la barrière hémato-encéphalique ↑ liquide inflammatoire extravasculaire autour des lésions, qui apparaît hyperintense/brillant Lésions s’étendent autour des veines, créant les lésions ovoïdes charactéristiques Plaques hyperintenses perpendiculaires périventriculaires classiques en T2/FLAIR suivant les veins médullaires – ‘Doigts de Dawson’ Lésion hyperintense du pédoncle cérebelleux moyen en T2/FLAIR dans une localisation classique de la SEP Légende: Physiopathologie Mécanisme Signe/Symptôme/Résultats de Laboratoire Complications Publié 25 octobre 2020 sur www.thecalgaryguide.com

pleural-effusions-pathogenesis-and-anterior-posterior-chest-x-ray-findings

Pleural Effusions: Pathogenesis and Anterior-Posterior Chest X-Ray Findings Decubitus chest x-ray view causes fluid to accumulate on ipsilateral side. (Most sensitive view for small effusions) Excess fluid accumulation within pleural space that is gravity- dependent/free- flowing Large accumulation of fluid pressing against lung tissue and mediastinum Fluid layering (i.e. opacification) between lung and chest wall Author: Sravya Kakumanu Reviewers: Reshma Sirajee, Tara Shannon *Stephanie Nguyen, *Shelley Spaner * MD at time of publication Transudative pleural effusion *See Pathogenesis and Clinical Findings of Transudative Pleural Effusions slide Exudative pleural effusion *See Pathogenesis and Clinical Findings of Exudative Pleural Effusions slide Fluid accumulation at bottom of pleural space in anterior- posterior chest x- ray Lung atelectasis (lung collapse) Fluid is denser than air and appears white on x-ray ↓ Pressure and occupied space in thoracic cavity Meniscus sign (concave line above opacification) Opacification of affected pleural space Blunting of costophrenic angles Diaphragmatic silhouette sign (sharp diaphragm edge obscured by fluid) Mediastinal shift towards atelectic lung Contralateral mediastinal shift (when no lung atelectasis) Contralateral tracheal deviation Pleural infections ↑ Inflammation at infection site à↑ permeability of parietal pleura endothelium Bacterial invasion into pleural space from pulmonary parenchyma ↑ Migration of neutrophils and release of inflammatory cytokines in pleural space Inflammation ↑ activation of coagulation cascade and ↓ fibrinolytic activity ↑ Deposition of fibrin clots/membranes within pleural space creating septations Loculated pleural effusion/empyema (fluid stuck within septations within the pleural space) Opacification does not follow gravity Effusion does not move in decubitus view Pleural thickening (whitening of lung perimeter from fibrin deposition - more visible on CT scan) More rounded margins with chest wall/fissures Note: ~175-500mL of fluid may need to accumulate before being visible on an Anterior-Posterior Chest X-Ray Image credit: https://radiopaedia.org/cases/pleural-effusion-7 Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 22, 2022 on www.thecalgaryguide.com

gout-pathogenesis-of-x-ray-findings

Gout: Pathogenesis of X-Ray findings Authors: Omer Mansoor, Nameerah Wajahat Reviewers: Reshma Sirajee, Tara Shannon *Stephanie Nguyen, *Shelley Spaner *MD at time of publication Hyperuricemia See hyperuricemia slide for mechanism ↑ Uric acid concentration in blood leaks into joints as monosodium urate (MSU) crystals Uric acid crystallizes due to lower temperature, change in pH, mechanical stress and other synovial factors Crystals found more commonly in 1st MTP joint > ankle > wrist MSU deposits within the bone producing intra-osseus tophi (stone-like deposits of crystals) MSU deposits in soft tissue and bone ↑ Inflammatory marker recruitment causes granulomatous inflammation Osteoclasts (↑ bone resorption) are activated, and osteoblasts (↑ bone formation) are inhibited at site of inflammation Marked localized bone loss ‘Rat Bite’ erosions Intra-osseus bone lesion (rare and non-specific for gout) Joint effusions may be seen on x-ray as an early finding in the acute phase of gout Soft Tissue Tophi (appear cloudy and can hide other x-ray findings) Normal bone density and preserved joint space (until late in the disease) Overhanging sclerotic margins Bone remodelled in an outward fashion to create the edge Punched out lytic bone lesions Appear as circular ‘hole punches’ in bone Note: Repeated episodes of gout must occur for 5 to 10 years before most joint changes may be seen on x-ray Image credit: Radiopaedia Legend: Pathophysiology Mechanism Sign/Radiographic Findings Complications Published June 7, 2022 on www.thecalgaryguide.com

Epilepsy Pathogenesis

Epilepsy: Pathogenesis Genetic susceptibility Angelman syndrome, Fragile X syndrome, Tuberous sclerosis, neurofibromatosis Chromosomal abnormalities cause abnormal neural patterns Neural Cerebral palsy, focal cortical dysplasia Malformation of cortical development Cerebrovascular Intracranial hemorrhage, ischemic stroke Other Acquired Head trauma, cerebral infection (i.e., HSV1, VZV, cysticercosis) Neoplasm Metabolic Inborn errors of metabolism Inherited enzyme deficiencies Neurodegenerative Alzheimer’s Disease Protein-rich plaque build-up and brain atrophy Inflammation and formation of scar tissue irritates neural tissue Infiltration of mass, grey matter irritation Damage to the brain and subsequent alteration of neuronal circuitry Neurotransmitter imbalances (i.e. ↑ glutamate, ↓ GABA, ↓ serotonin, ↓ dopamine, ↓ noradrenaline) Abbreviations: • HSV1 – Herpes Simplex Virus 1 • VZV – Varicella Zoster Virus ↑ Inflammatory cytokines (e.g. interleukin-6, tumor necrosis factor-α) Altered neurogenesis and gliosis Ion channel and receptor dysfunction causes imbalance of ion channel charges Authors: Keerthana Pasumarthi Christopher Li Reviewers: Negar Tehrani, Ephrem Zewdie, Ran (Marissa) Zhang, Carlos R. Camara-Lemarroy* * MD at time of publication Neurons fire in burst activity (referred to as paroxysmal depolarization shift) and often in groups (hypersynchrony) Abnormal neural activities eventually create self-reinforcing circuits and transform neural network over time Injuries from falls, bumps, operating heavy machinery Involuntary contractions Loss of consciousness Post-ictal confusion Recurrent seizures Sudden Unexplained Death of Epilepsy Patient (SUDEP) Loss of airway reflexes Aspiration of saliva or food contents Aspiration Pneumonia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 5, 2022 on www.thecalgaryguide.com

exudative-pleural-effusions-pathogenesis-and-lab-findings

Exudative Pleural Effusions: Pathogenesis and Lab Findings Authors: Sravya Kakumanu Reviewers: Ben Campbell *Tara Lohmann * MD at time of publication Chylothorax Damage to thoracic duct Leakage of lymphatic fluid into pleural space Pulmonary embolism Clot obstructs blood flow to lung Infarcted lung tissue Lung infection (e.g. pneumonia, tuberculosis) Lung infection signals inflammatory response Systemic Lupus Rheumatoid Erythematosus (SLE) arthritis (RA) Autoimmune antibodies localize to pleura Pleural tumors (primary or secondary from metastatic cancer) Inflammatory cells migrate to affected site and release cytokines ↑ Permeability of pleural capillaries ↑ Fluid leakage across capillaries Exudative Pleural Effusion Cancer invades lymphatic drainage of pleural space (PS) ↓ Drainage of pleural fluid (PF) from pleural space If infectious etiology Tumor invasion = inflammatory response See Pleural Effusions: X-ray Findings and Physical Exam Findings of Lung Diseases slides ↑ Permeable pleural capillaries allow ↑ protein and cell leakage into pleural space If pleural tumour: Release of cancer cells into pleural space Cancer cells on PF cytology 60-75% sensitive for malignancy If rheumatoid arthritis: Release of auto-antibodies into pleural space Auto-antibodies initiate inflammatory response in pleural space ↑ Inflammatory cells have ↑ glucose metabolism in pleural space Sterile PF with mildly elevated white blood cells, normal pH, normal glucose ↑ Inflammation at infection site damages endothelium of pleura Pleural Infection Stage I: Simple Parapneumonic Effusion ↑ Inflammatory cells and bacterial cells in pleural space have ↑ glucose metabolism in pleural space Bacterial invasion from infected parenchymaà pleural space < 40mg/dL glucose in PF ↑ Activation of coagulation cascade and ↓ fibrinolytic activity ↑ Deposition of fibrin clots/membranes within pleural space creates loculated effusion (compartmentalized effusion due to septations in pleural space) ↑ Production of lactate dehydrogenase (LDH) (LDH maintains NAD+ supply during ↑ glucose metabolism) ↑ CO2 production pH of PF < 7.20 ↑ CO2 production pH of PF < 7.20 < 3.3mmol/L glucose in PF Pleural Infection Stage II: Complicated Parapneumonic Effusion Loculated effusion OR bacteria present OR ↓ pH + ↓ glucose ↑ Fibroblast proliferation creates thickened pleura ↑ Pus in pleural space Pleural Infection Stage III/Empyema: Loculated effusion and pus in pleural space PF/serum protein ratio ≥ 0.5 PF/serum LDH ratio ≥ 0.6 Light’s Criteria: Any criteria can be met to be an exudative pleural effusion PF LDH ≥ 2/3 upper limit of normal Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 9, 2022 on www.thecalgaryguide.com

thrombose-veineuse-profonde-soupconne-tvp-pathogenese-et-complications

Thrombose veineuse profonde soupçonné (TVP) Auteurs: Dean Percy Yan Yu Rédacteur: Tristan Jones Julia Heighton Man-Chiu Poon* Lynn Savoie* Traducteurs: Sophia Shah Sylvain Coderre* *MD à la publication La grossesse, contraceptifs oraux Pathogénèse et complications Activation plaquettaire ↑ formation de caillots Maladies héréditaires Anomalie congénitale de la coagulation (p.e. facteur V Leiden, facteur II muté, déficit en protéine S/C) ↑ capacité de coagulation Notes: • TVP provoque une embolie pulmonaire, le thrombus artériel provoque un accident vasculaire cérébral • TVP précédente est un facteur de risque de TVP courante Malignité Libération anormale de cytokines favorisant la coagulation Traumatisme/opération Blessure systémiqueà activation de la cascade de coagulation État d'hypercoagulabilité↑ capacité du sang à coaguler lors de la stimulation Oestrogène favorise l'hypercoagulabilité, surtout en présence d'autres risques Hypertension Bactéries Valve artificielle Endommage les parois des vaisseaux Adhèrent/ envahissent / vaisseaux Surface anormale Blessure de vaisseau Expose le facteur tissulaire sur les cellules endommagées /sous-endothélium pour la liaison au FvW Triade de Virchow Stase veineuse ↓ débit sanguins au site de la lésion vasculaireà concentration des facteurs de coagulation sanguine sur ce site La graisse contient plus d'aromatase: ↑ d'androgènesà œstrogènes mode de vie sédentaire, mauvais retour veineux Obésité Les caillots se produisent généralement dans les veines des jambes 1. Les veines larges et profondes permettent l'accumulation de sang 2. Retour veineux des jambes est contre la gravité 3. Valves dans les veines des jambes enclins au refoulement ↓ mouvement musculaire = ↓ débit sanguin Fracture, immobilisation, alitement, long tour d’avion/ de véhicule Destruction de la valve veineuse par un caillot Insuffisance veineuse Les caillots empêchent le sang à retourner au cœur. L'accumulation de sang dans une jambe entraîne l’œdème unilatéral et l’inflammation veineuse (rougeur, chaleur, sensibilité) Le caillot s'embolie dans les poumons Thromboembole -*Embolie pulmonaire (complication aiguë mortelle) - Hypertension pulmonaire thromboembolique chronique Légende: Physiopathologie Mécanisme Signe/Symptôme/Résultats de Laboratoire Complications Publié 15 juin 2019 sur www.thecalgaryguide.com

patellar-tendon-rupture-pathogenesis-and-clinical-findings

Patellar Tendon Rupture: Pathogenesis and clinical findings Author: Molly Joffe Reviewers: Liam Thompson, Alyssa Federico, Tara Shannon, Gentson Leung* *MD at time of publication Chronic disease (e.g. renal failure, gout, rheumatoid arthritis, and diabetes) Repetitive activities involving rapid knee flexion and extension Tendon inflammation and micro-tearing Fluoroquinolone (antibiotic class) use Smoking Immobilization of knee ↓ Muscle and tendon flexibility and strength Steroid use (including intraarticular injections) Changes in collagen fibrils composing tendon (exact mechanism unknown) Disrupted blood supply to tendon and poor healing Compromised integrity and strength of the tendon Sudden heavy load on flexed knee while foot is planted Quadriceps muscles contract while lengthening (eccentric contraction)àforce exceeds tendon strength Patellar tendon innervated by common peroneal (fibular) nerve Nociceptors (pain receptors) within tendon activated by tendon rupture Pain and tenderness below the patella Collagen fibres in tendon tear Tearing or popping sensation at time of injury Patellar Tendon Rupture Tendon/Ligament detaches from bony attachment on patella or tibial tubercle No connection of quadriceps to tibia via patellar tendon ↑ Force on tibial tubercle during tendon detachment Avulsion fracture of tibial tubercle Trauma to tendon ruptures surrounding blood vessels Coagulation cascade and inflammatory mediators released at rupture site Quadriceps muscles unable to stabilize patellar tracking Instability of knee joint Quadriceps muscle tension pulls patella upwards with no resistance from patellar tendon Patellar tendon cannot use distal attachment site for leverage Knee extensor muscles unable to effectively contract Knee buckling Abnormal gait Patella alta (high sitting patella) on X-ray Palpable gap below the patella Bruising below the patella Swelling below the patella ↑ Risk of falls Loss of patellar reflex Inability to perform a straight leg raise (hip flexes and knee cannot remain straight) Hematoma (blood collection under the skin) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 28, 2022 on www.thecalgaryguide.com

ascending-cholangitis-pathogenesis-clinical-findings

Ascending Cholangitis: Pathogenesis and clinical findings Authors: Brandon Hisey, Neel Mistry Reviewers: Alec Campbell, Vina Fan, Ben Campbell, Kelly Burak*, Eldon Shaffer* * MD at time of publication Reflux of biliary contents into the vascular system (cholangiovenous reflux) Bacteria ascends into biliary tract from duodenum via Sphincter of Oddi Gallstone in the common bile duct Stricture of biliary/hepatic ducts Biliary / pancreatic duct malignancy Biliary obstruction (partial bile duct obstruction) ↓ Excretion of bilirubin into bileà ↑ bilirubin in blood ↑ Serum bilirubin Deposition of bilirubin in the skin and mucous membranes Jaundice*† Parasites in bile duct (E.g. Clonorchis) Complication of endoscopic retrograde cholangiopancreatography (ERCP) Bile accumulates in biliary tract Bile duct dilation on ultrasound Sludge (bile precipitants) impact bile ducts worsening obstruction Obstruction & detergents in bile inflame ductal mucosa. Inflammation then spreads to adjacent structures Stimulates phrenic (C3-C5) and foregut autonomic nerves (T5-T8) Dull right upper quadrant pain*† radiating to back and right shoulder ↑ Intra-biliary pressure Impaired forward flowà ↑ backflow of bile Impaired bile secretion damages ductal epithelium of the biliary tract Damaged ductal epithelium leaks ALP and GGT (enzymes) into blood ↑ Serum ALP and GGT ↑ Permeability of bile ductules Reduced flushing of bile out to duodenum Inflammatory response triggered Fever*† ↑ WBCs Tachycardia Hypotension† Confusion† Oliguria Bacterial translocation from biliary tract into blood Bacteremia Massive systemic inflammatory response Septic Shock (see Distributive Shock slide) * Charcot’s triad ~20% of cases | † Reynolds’ pentad ~7% of cases Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published November 18, 2015; Updated August 31, 2022 on www.thecalgaryguide.com

acute-lower-gi-bleeds-pathogenesis-and-clinical-findings

Acute Lower GI Bleeds: Pathogenesis and Clinical Findings Diverticulosis Formation of diverticula (outpouchings of the bowel wall) Intestinal vessels are stretched over the domes of the diverticula Angiodysplasia Formation of dilated, thin- walled vessels in GI tract mucosa/ submucosa Colorectal Cancer Infectious Colitis Invasion of bacteria and/or bacterial toxins into intestinal wall Cell damage and cell death Sloughing off of intestinal epithelial cells Ischemic Colitis ↓ Blood flow to a portion of the colon Lack of oxygen delivery to colon wall Necrosis (cell death) in the colon wall Inflammatory Bowel Diseases (Note: these are chronic diseases and rarely present with acute lower GI bleed) New, extremely friable blood vessels develop within the tumor Malignant tissue invades the colon wall and disrupts colonic blood vessels Crohn Disease Immune- mediated full thickness inflammation of bowel wall Ulcer formation and disruption of intestinal vessels Ulcerative Colitis Recurrent immune- mediated inflammation of colon mucosa Authors: Miranda Schmidt Illustrator: Mizuki Lopez Reviewers: Vina Fan, Ben Campbell, Kerri Novak* * MD at initial time of publication Acute Lower GI Bleed ↑ Risk for vessel damage and rupture Blood travels rapidly through GI tract Hematochezia (bright red blood per rectum) May result in significant blood loss Blood from the small intestine or right colon travels a longer distance through the GI tract Bacteria in the GI tract has time to oxidize hemoglobin in the blood Oxidization makes blood a darker color Melena (rare in a lower GI bleed) (tarry black stool) Inferior Vena Cava Diaphragm Esophagus Loss of red blood cells results in a loss of hemoglobin (a component of red blood cells) Fluid from the extravascular space moves into the blood vessels to maintain vascular volume Fluid is administered in a healthcare setting to compensate for blood loss Hypovolemic Shock (rare in a lower GI bleed) (↓ Oxygen delivery to tissues due to low blood volume) See “Hypovolemic Shock” slide for signs and symptoms Lower GI Bleeds are intra-luminal GI tract bleeds that occur anywhere distal to the ligament of Treitz (transition between duodenum and jejunum) After 24 hours, the addition of fluid to the intravascular space dilutes hemoglobin in the blood Normocytic Anemia Duodenum Ligament of Treitz Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 31, 2022 on www.thecalgaryguide.com

quadriceps-tendon-rupture-pathogenesis-and-clinical-findings

Quadriceps Tendon Rupture: Pathogenesis and clinical findings Author: Molly Joffe Reviewers: Liam Thompson, Alyssa Federico, Tara Shannon, Gentson Leung* *MD at time of publication Repetitive activities involving, rapid, active flexion and extension of the knee Quadriceps tendon inflammation and micro-tearing Immobilization of leg/knee Steroid use (including intraarticular injections) Quadricep muscles atrophy ↓ Quadricep muscle strength Smoking Chronic disease (e.g. renal failure, gout, rheumatoid arthritis, and diabetes) Fluoroquinolone (antibiotic class) use Changes in collagen fibrils composing tendonàimpaired tendon strength (exact mechanism unknown) Quadriceps tendon shortens ↓ Quadricep tendon flexibility Disrupted blood supply to quadriceps tendon and poor healing Compromised integrity of the quadriceps tendon and ↓ strength Sudden heavy load on flexed knee while foot is plantedàquadriceps muscles contract while lengthening (eccentric contraction) Force on quadriceps tendon exceeds its strength Quadriceps Tendon Rupture Tendon detaches from bony attachment on patella ↑ Force on patella during quadriceps tendon detachment Collagen fibres in quadriceps tendon tear No connection of quadriceps to tibia via quadriceps tendon Patellar tendon tension pulls patella downwards with no resistance from quadriceps muscles Quadriceps tendon innervated by common peroneal (fibular) nerve Nociceptors (pain receptors) within tendon activated by tendon rupture Pain and tenderness above the patella Trauma to tendon ruptures blood vessels Coagulation cascade and inflammatory mediators released at rupture site Quadriceps muscles unable to stabilize patellar tracking Knee joint instability Patella baja (low sitting patella) on X-ray Palpable gap above the patella Loss of patellar reflex Patellar tendon cannot use proximal attachment site for leverage Knee extensor muscles unable to effectively contract Inability to perform a straight leg raise (hip flexes while knee cannot remain straight) Bruising above the patella Swelling above the patella Avulsion fracture of patella Tearing or popping sensation at time of injury Knee buckling Abnormal gait ↑ Risk of falls Hematoma (blood collection under the skin) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 2, 2022 on www.thecalgaryguide.com

microscopic-colitis-pathogenesis-and-clinical-findings

Microscopic Colitis: Pathogenesis and clinical findings Genetic Author: Tony Gu, Kayleigh Yang Reviewers: Yoyo Chan, Vina Fan, Ben Campbell, Dr. Edwin Cheng* * MD at time of publication Release of cytokines (e.g. interferon gamma (IFNγ)) Downregulation of intestinal tight junction proteins ↓ Epithelial barrier function ↑ Transmucosal permeability Infiltration of bacteria or antigens ↑ Expression of nuclear factor kappa B (NF-kB) in colonic epithelial cells NF-kB increases transcriptional activity in specific genes ↑ Inflammatory molecules (histamine, prostaglandins, and nitric oxide) in epithelium predisposition Unknown trigger ↑ Transforming growth factor beta 1 (TGF- β1) and vascular endothelial growth factor (VEGF) expression in colonic epithelial cells Equilibrium shift to more production of collagen (fibrinogenesis) than breakdown (fibrinolysis) Drug exposure (e.g., non- steroidal anti- (+) inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs)) Inflammation and accumulation of immature subepithelial collagen matrix Subtype: Collagenous Colitis Intestinal mucosal inflammation Subtype: Lymphocytic Colitis characterized by a colonic subepithelial characterized by intraepithelial collagen band on histology lymphocytic infiltrates on histology Microscopic Colitis Intestinal epithelial damage Malabsorption of nutrients (including bile acids) Weight loss ↑ Intestinal transmucosal permeability Water drawn into lumen through osmosis Ions and water back leak into intestinal lumen Non-bloody watery diarrhea Dehydration and electrolyte disturbances Continuous release of inflammatory mediators Peripheral afferent nerve sensitization Visceral hypersensitivity Abdominal pain Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 8, 2018, Updated October 18, 2022 on www.thecalgaryguide.com

copd-findings-on-posterior-anterior-and-lateral-chest-x-ray-findings

Authors: Shayan Hemmati COPD: Findings on Posterior-Anterior and Lateral Chest X-ray Findings Reviewers: Reshma Sirajee, Sravya Kakumanu, Tara Shannon, *Stephanie Nguyen, *MD at time of publication Chronic Obstructive Pulmonary Disease (COPD) See Pathogenesis of COPD Slides Findings of COPD may not be apparent on chest X-ray early within the disease Lung inflammation causes proteolytic destruction of lung parenchyma (part of lungs involved in gas exchange) Alveolar walls are damagedàformation of fragile enlarged sacs of air called bullae Rupture of bullae due to weak alveolar walls Air leaves alveola and enters pleural space Pneumothorax See Primary Spontaneous Pneumothorax slide Vasoconstriction of pulmonary arteries to shunt blood to better ventilated areas Pulmonary hypertension See Pathogenesis of Pulmonary Hypertension slide ↑ Pressure within pulmonary arteries Enlargement of pulmonary arteries Hilar enlargement Lung hyperinflation (defined as 10 posterior ribs above the diaphragm level on the midclavicular line) ↑ Lucency of the lung field, ↓ lung markings (unless COPD is of chronic bronchitis phenotype) ↑ Size of retrosternal airspace ↑ Anterior – posterior (AP) diameter (“Barrel Chest”) Flattening of hemidiaphragms 12 3 4 5 6 7 8 9 10 Poorly ventilated areas of lung Hyperinflation as air becomes trapped in damaged lungs ↑ Total volume of air within the chest Airway fibrosisà bronchial wall thickening (yellow arrow heads) Air is less dense than soft tissue and vessels so it appears black ↑ Pressure anteriorly on sternum ↑ Pressure posteriorly on thoracic wall ↑ Pressure posteriorly on diaphragms PA Bullae sometimes visible on X-ray (focal areas of lucency with spread out vascular markings) Image credit: Bronchial wall thickening image courtesy of Dr. Ashley Davidoff Image credit: Radiopaedia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 26, 2022 on www.thecalgaryguide.com

Granulomatosis with Polyangiitis Pathogenesis

Granulomatosis with polyangiitis: Pathogenesis Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication Drugs Thiol- and hydrazine-containing medications (e.g., hydralazine, propylthiouracil, allopurinol) Environmental exposures Silica dust, cigarette smoke, infections (Staphylococcus aureus) Genetic factors Alpha-1 antitrypsin deficiency, proteinase 3 gene mutation ↑ Production of cytokines and antineutrophil cytoplasmic antibodies (ANCAs) (mechanism unknown) Cytokines bind to endothelial cells (that line blood vessels) and neutrophils, priming them Proteinase 3 (PR3), an enzyme that degrades extracellular matrix proteins, migrates from neutrophil granules to neutrophil cell surface Circulating ANCAs bind to PR3 on neutrophils PR3 stimulates maturation of dendritic cells in lungs Dendritic cells present antigen (PR3) to naïve CD4+ T cells in peripheral lymph nodes T cells differentiate into type 1 and type 17 helper T cells (Th1 and Th17 cells) Th1 and Th17 cells secrete cytokines (interferon γ (INF-γ) and tumor necrosis factor α (TNF-α)) in lungs Secreted cytokines trigger macrophage maturation Formation of granulomas (giant cells with central necrosis surrounded by plasma cells, lymphocytes, and dendritic cells) primarily in lungs and upper airways ANCA-activated neutrophils release proinflammatory cytokines, attracting more neutrophils to endothelium (blood vessel wall) ANCA-activated neutrophils undergo firm adhesion to endothelium ANCAs stimulate ↑ secretion of proteolytic enzymes and reactive oxygen species from neutrophils Endothelial damage and tissue injury Granulomatosis with polyangiitis (GPA) ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms with involvement of multiple organ systems (see slide on clinical findings) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com Granulomatosis with polyangiitis: Clinical findings Inflammation-mediated endothelial damage and granuloma formation (see slide on pathogenesis) Granulomatosis with polyangiitis (GPA) Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms Fever, unintentional weight loss, night sweats, arthralgias Skin involvement Inflammation of cutaneous vessels Systemic inflammation obstructing blood flow, with granulomatous lesions primarily in upper airways and lungs Ear, nose, and throat involvement ↑ C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (markers of inflammation) Necrotizing granulomas on biopsy of affected tissue Positive PR3-ANCA/c-ANCA blood test (antibodies present in ~90% of patients, described in GPA Pathogenesis slide) Renal involvement Inflammation of renal vessels Rupture of basement membrane (layer that filters blood from glomerular capillaries into Bowman’s capsule) Pauci-immune glomerulonephritis (see Nephritic Syndrome slide) Rapidly progressive glomerulonephritis Eye involvement Inflammation of ocular tissue Conjunctivitis Scleritis/ episcleritis (painful red eye) Lower respiratory tract involvement Inflammation of pulmonary vessels Vessel occlusion and ischemia Skin necrosis Vessels burst and blood pools under skin Round and retiform (net- like) palpable purpura of lower extremities Granulomatous destruction of nasal cartilage Collapse of nasal bridge Saddle nose deformity Inflammation of paranasal sinus and nasal cavity vessels ↓ Perfusion of lungs Dyspnea Damage to interstitial capillaries Hemoptysis Diffuse alveolar hemorrhage Rhinitis/ sinusitis Granulomatous obstruction of eustachian tube Otitis media (see Otitis Media slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com

Granulomatosis with polyangiitis: Clinical findings

Granulomatosis with polyangiitis: Clinical findings Inflammation-mediated endothelial damage and granuloma formation (see slide on pathogenesis) Granulomatosis with polyangiitis (GPA) Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms Fever, unintentional weight loss, night sweats, arthralgias Skin involvement Inflammation of cutaneous vessels Systemic inflammation obstructing blood flow, with granulomatous lesions primarily in upper airways and lungs Ear, nose, and throat involvement ↑ C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (markers of inflammation) Necrotizing granulomas on biopsy of affected tissue Positive PR3-ANCA/c-ANCA blood test (antibodies present in ~90% of patients, described in GPA Pathogenesis slide) Renal involvement Inflammation of renal vessels Rupture of basement membrane (layer that filters blood from glomerular capillaries into Bowman’s capsule) Pauci-immune glomerulonephritis (see Nephritic Syndrome slide) Rapidly progressive glomerulonephritis Eye involvement Inflammation of ocular tissue Conjunctivitis Scleritis/ episcleritis (painful red eye) Lower respiratory tract involvement Inflammation of pulmonary vessels Vessel occlusion and ischemia Skin necrosis Vessels burst and blood pools under skin Round and retiform (net- like) palpable purpura of lower extremities Granulomatous destruction of nasal cartilage Collapse of nasal bridge Saddle nose deformity Inflammation of paranasal sinus and nasal cavity vessels ↓ Perfusion of lungs Dyspnea Damage to interstitial capillaries Hemoptysis Diffuse alveolar hemorrhage Rhinitis/ sinusitis Granulomatous obstruction of eustachian tube Otitis media (see Otitis Media slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com

Erythema multiforme (EM): Pathophysiology and clinical findings

Erythema multiforme (EM): Pathophysiology and clinical findings Infectious agents (cause >90% of EM) Herpes simplex virus types 1 and 2 Mononuclear cells transport herpes simplex virus DNA fragments to keratinocytes in epidermis Herpes simplex virus-specific CD4 T-cells of the immune system are recruited to the epidermis CD4 T-cells release interferon-gamma (a pro-inflammatory cytokine) in response to viral antigens in keratinocytes in the epidermis Lymphocytes infiltrate along the dermal-epidermal junction of the skin Lymphocytes create an inflammatory and edematous environment Keratinocytes irreversibly degenerate and undergo apoptosis and necrosis Formation of inflammatory epidermal lesions Authors: Ayaa Alkhaleefa Reviewers: Ben Campbell Damilola Omotajo Jori Hardin* *MD at time of publication Drugs (a rare cause of EM) Non-steroidal anti- inflammatory drugs i.e. diclofenac sodium Antibiotics i.e. TMP- SMX Topical 5% Imiquimod, used to treat actinic keratoses Activate tumour-necrosis-factor- alpha, an inflammatory cytokine Skin Epidermal layer Dermal-Epidermal Junction Dermal layer Triggering agent (infection, drugs) Immune-mediated inflammation and epidermal tissue damage Erythema multiforme Inflammation ↑ capillary blood flow in dermis Red colouring of skin in the area Centre of lesions contain a necrotic core Inflammatory edema causes margins around necrosis to form a raised and pale ring Inflammation stimulates cutaneous itch receptors Erythematous, papular, target-shaped, pruritic lesions on mucosal and acral (palms of hands, soles of feet) sites and face Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 29, 2022 on www.thecalgaryguide.com

rheumatoid-pneumoconiosis-caplans-syndrome-pathogenesis-and-clinical-findings

Rheumatoid Pneumoconiosis (Caplan’s Syndrome): Pathogenesis and clinical findings Authors: Christopher Li Keerthana Pasumarthi Reviewers: Daniela Urrego, Ben Campbell, Liam Martin* * MD at time of publication Dust-exposed occupation (e.g. coal, asbestos, silica) ↑ Accumulation of dust particles in lungs Dust (e.g. silica) mobilizes from the lungs to other organs such as the kidneys, lymph nodes, and spleen Accumulation of silica in other organs which activate the immune system to secrete cytokines, chemokines, and lysosomal enzymes Activation of antigen- presenting and antibody- producing cells Increased risk to produce autoantibodies Increased risk for autoimmune conditions such as rheumatoid arthritis See slide: Rheumatoid Arthritis (RA): Extra- articular manifestations for mechanism of systemic inflammation See slide Pneumoconioses: Pathogenesis and clinical findings for mechanism Note: Rheumatoid arthritis may precede lung nodules or develop later in the course Rheumatoid arthritis Systemic autoimmune inflammatory disease that mainly involves synovial joints (+) Alveolar macrophages and neutrophils ingest dust particles ↑ Inflammation and cytokine production in pulmonary parenchyma (e.g. interleukin-1, tumor necrosis factor-α) Rheumatoid pneumoconiosis Interstitial lung disease, with characteristic nodules, resulting from the interaction between dust inhalation and rheumatoid arthritis inflammation Cytokines recruit histiocytes, neutrophils, lymphocytes, and fibroblasts to the area to produce a zone of inflammation around the dust-containing cell Necrosis and apoptosis of dust-containing cells, macrophages, and surrounding collagen Necrotic cells are digested by new macrophages to restart the process Production of nodules that contain a central necrotic area surrounded by alternate layers of dust and necrotic tissue (Caplan nodules) Hyperactive immune response to foreign materials in lungs Multiple concentric rings of dust seen histologically on light microscopy 0.5-5 cm rounded opacities on chest X-ray in periphery of lungs See slide on Pneumoconioses for symptoms and pulmonary function test results Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 17, 2022 on www.thecalgaryguide.com

Acute and Chronic Gastritis: Pathogenesis and clinical findings

Acute and Chronic Gastritis: Pathogenesis and clinical findings Author: Oswald Chen Reviewers: Vina Fan, Ben Campbell, Eldon Shaffer* * MD at time of publication Infectious Helicobacter pylori (most common) Noninfectious NSAIDs, alcohol, gastric reflux Stress Critical illness, trauma Gastric ulceration (see Peptic Ulcer Disease slide) ↓ Gastric mucosal defense (↓ secretion of prostaglandins and mucus) Acid erodes gastric mucosa Inflammatory cells (primarily neutrophils) infiltrate site of injury Acute Gastritis Acute inflammation of gastric mucosa Inflammatory cells (primarily lymphocytes and plasma cells) accumulate in gastric mucosa Autoimmune Metaplastic Environmental Metaplastic Atrophic Gastritis (AMAG) Atrophic Gastritis (EMAG) Atrophic Gastritis Chronic inflammation of gastric mucosa Inflammatory cells destroy gastric glandular epithelial cells Gastric mucosal atrophy and metaplasia (replacement of gastric mucosal cells with intestinal epithelial cells, commonly goblet cells) Hypochlorhydria (parietal cell loss → ↓ hydrochloric acid secretion) ↓ Iron absorption Iron deficiency anemia (see Iron Deficiency Anemia slide) Activation of chemoreceptors and mechanoreceptors Activation of visceral nociceptors Visceral afferents stimulate chemoreceptor trigger zone of medulla Nausea/ vomiting Autoimmune Associated with human leukocyte antigens HLA-B8 and HLA-DR3, which are proteins expressed on immune cell surface Antibodies destroy parietal cells and intrinsic factor in gastric body and fundus Epigastric pain (typically burning or gnawing) Dyspepsia (abdominal discomfort after eating, often with early satiety and bloating) Parietal cell loss → ↓ intrinsic factor → ↓ vitamin B12 absorption Vitamin B12 deficiency (see Vitamin B12 Deficiency slide) Macrocytic Peripheral anemia neuropathy ↓ Gastric acidity leads to ↓ inhibition of G cells in antrum Hypergastrinemia (↑ gastrin release from G cells) Gastrin binds to cholecystokinin-B (CCK-B) receptors on parietal and enterochromaffin-like (ECL) cells of gastric body ↑ CCK-B signaling leads to ↑ cell proliferation and ↓ cell death (↓ apoptotic activity) Hyperplasia (↑ number of cells) Low-grade dysplasia (disordered growth of epithelium) High-grade dysplasia Carcinoid tumor (0.7% of cases) Malignancy arising from ECL cells Gastric adenocarcinoma (0.3% of cases) Malignancy arising from gastric epithelial cells Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 15, 2022 on www.thecalgaryguide.com

Achalasia: Findings on Fluoroscopy with Barium Swallow

Achalasia: Findings on Fluoroscopy with Barium Swallow Authors: Nameerah Wajahat, Omer Mansoor, Aly Valji Reviewers: Tara Shannon, Reshma Sirajee, Stephanie Nguyen* *MD at time of publication Barium swallow performed (patient swallows barium contrast, a radiopaque agent, which outlines the gastro-intestinal (GI) tract during fluoroscopy) Primary Achalasia (idiopathic) Secondary (Pseudo) Achalasia (due to another disease process such as tumor, Chaga’s disease, diabetes mellitus) Achalasia Secondary disease processes can cause denervation or nerve dysfunction of esophageal myenteric plexus (EMP). Tumors can obstruct the lumen and infiltrate the EMP. Visual differences from primary achalasia Look for fixed abnormalities and/or mucosal irregularities and shouldering in the setting of a tumor Nerves controlling the lower esophagus are damaged, making it difficult for food and liquids to pass the esophagus See “Achalasia: Pathogenesis and Clinical Findings” for full pathogenesis of primary and secondary achalasia Inflammation and degeneration of nerves in the wall of esophagus Dysfunction of the esophageal myenteric plexus (network of nerves in the GI tract responsible for peristalsis and sphincter relaxation) Incomplete relaxation of the Loss of peristalsis in distal lower esophageal sphincter (LES) esophagus Barium has difficulty passing through the LES to the stomach Barium outlines the GI tract, following esophageal abnormalities Normal findings Esophageal Dilatation Occurs upstream of narrow LES Bird Beak Sign / Rat Tail Sign Smooth narrowing of the distal esophagus Incomplete LES relaxation Barium Swallow may be normal in some patients with achalasia. Esophageal manometry (gold standard for diagnosis) or upper endoscopy can be considered instead. Image Source: Radiopaedia Legend: Pathophysiology Mechanism Radiographic Findings Complications Published November 9, 2022 on www.thecalgaryguide.com

popliteal-bakers-cyst-pathogenesis-and-clinical-findings

Popliteal (Baker’s) Cyst: Pathogenesis and clinical findings Authors: Liam Thompson, Megan Ure Reviewers: M. Patrick Pankow, Tara Shannon, Reza Ojaghi, Usama Malik, Dr. Gerhard Kiefer* * MD at time of publication Repeated contraction of muscles surrounding the bursaàmicro trauma to bursa Inflammatory response Idiopathic (common: kids 4-7 years old) Bursa located between medial head of gastrocnemius and semimembranosus tendon Accumulation of inflammatory fluid into the bursa forming a cyst Meniscal Tear Tear creates a channel between joint capsule and bursa posterior to the knee joint Rheumatoid Arthritis Auto-immune mediated inflammation of knee joint Osteoarthritis Destruction of articular cartilageà inflammation within knee joint See Osteoarthritis: Pathogenesis slide Damage to joint capsule and accumulation of inflammatory fluid Proteolytic enzyme dysregulation Local muscle action influences fluid flow and pressure changes Extra- articular Popliteal Cyst Fluid filled sac behind knee Usually asymptomatic (resolves spontaneously) Synovial joint herniates into popliteal fossa (most commonly medially)àaccumulation of fluid (synovial + inflammatory) into synovial herniation, forming a cyst Knee flexion Intra-articular Popliteal Cyst Known as “Baker’s cyst” Knee extension ↑ Muscle tension around cyst Channel between knee joint and cyst gradually closes with ↑ tensionàat full extension, no fluid flow between the joint and cyst (trapping the fluid in the cyst) ↓ Muscle tension around cyst Channel between knee joint and cyst opens Knee joint pressure becomes negative ↑ Fluid flow from cyst into knee joint ↓ Fluid in popliteal cyst Knee joint pressure becomes positiveà ↑ Fluid flow from knee joint into cyst (Posterior tibial nerve located lateral to the popliteal cyst and enervates posterior knee, calf, and bottom of foot) Posterior tibial nerve becomes entrapped by mass (cyst) Enlarging mass in posterior knee Cyst reaches maximum volume Pressure within cyst exceeds tensile strength of surrounding sac Fluid drains distally into calf Popliteal vein located lateral to cyst ↑ Venous pressure distal to cyst Popliteal vein occluded by mass Venous pooling distal to site of occlusion ↓ Space in posterior calf compartmentàcompression of calf muscles and posterior tibial nerve Ankle dorsiflexion ↑ pressure in compartment Positive Homan’s sign (discomfort with passive ankle dorsiflexion) Posterior plantar numbness Pain receptors (nociceptors) activated Posterior knee pain/pressure Cyst Rupture Abrupt and intense pain Stimulates inflammatory response Fluid pushed from veins into interstitial space Swelling and erythema (redness) in distal calf and foot Pseudo-Thrombophlebitis worse with extension or physical activity (shares symptoms with deep vein thrombosis but no associated clot) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 10, 2018, updated Nov 19, 2022 on www.thecalgaryguide.com

hypovolemic-shock

Hypovolemic Shock: Pathogenesis, Complications, and Clinical Findings Authors: Dean Percy Miranda Schmidt Reviewers: Yan Yu Tristan Jones Frank Spence* Ben Campbell Ayaaz Sachedina* * MD at time of publication Progressive ↓ in level of consciousness Pulseless Electrical Activity Acute Kidney Injury ↑ Reabsorption of salt and water in the kidney Oliguria (↓ urine output) Inflammation (pancreatitis, cirrhosis, post-operative, etc.) Inflammatory mediators ­ vessel permeability and fluid leaks out Trauma Ruptured vessels leak fluid into potential spaces Hemorrhagic losses (GI bleed, postpartum hemorrhage, etc.) ↓ Intravascular volume ↓ Venous return to the heart ↓ Cardiac output (blood pumped from the heart) Hypovolemic Shock ↓ Oxygen delivery to tissues due to low blood volume Insufficient organ perfusion Non-Hemorrhagic losses (dehydration, GI losses, skin losses / burns, renal losses, etc.) ‘Third Spacing’ of fluid (fluid located outside the intravascular or intracellular space; large collections can occur in the pelvis, thorax, GI tract, long bones of children, intra-abdominally, retroperitoneally) P = Q x R; less ‘flow’ in the vessels (Q), with vessels not constricting enough to maintain resistance (R)à pressure (P) will drop ↓ Blood Pressure Caution: young, healthy individuals can maintain blood pressure during circulatory collapse with ­ cardiac output and ­ vasoconstriction; do not use blood pressure as an indicator of shock severity in children Carotid sinus baroreceptors sense low blood pressure ↓ Carotid sinus inhibition of sympathetic nervous system Release of sympathetic catecholamines (epinephrine and ↓ Pressure in venous circulation Brain Heart Kidneys ↓ Blood in the right internal jugular vein ↓ Oxygen delivery to the brain ↓ Myocardial contractility (from lactic acidosis) ↓ Blood flow to kidneys ↓ Jugular Venous Pressure Catecholamines bind to beta-1 receptors in the sinoatrial node of the heart Beta-1 receptor activation causes ↑ heart rate Tachycardia norepinephrine) Catecholamines bind to and stimulate alpha-1 receptors in peripheral vessels Vasoconstriction of peripheral vessels ↓ Blood flow to peripheral tissue Catecholamines bind to and stimulate beta receptors in sweat glands Diaphoresis (sweating) In all body tissues Inadequate oxygen delivery ↓ ATP production ↑ Anaerobic metabolism ↓ Body temperature Impaired neurological functioning Renal ischemia Activation of the renin-angiotensin aldosterone system ↓ Glomerular filtration rate ↓ Clearance of lactic acid by the kidney ↑ Lactic acid production ↓ Rate of activity of clotting enzymes Lactic Acidosis Unknown mechanism Coagulopathy Hypothermia Trauma Triad of Death ↑ Capillary Cold, mottled refill time extremities Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 24, 2013, updated December 4, 2022 on www.thecalgaryguide.com

Ischemic Stroke: Pathogenesis

Ischemic Stroke: Pathogenesis Small artery occlusion Acute injury (<20mm diameter) of basal or brainstem penetrating arteries Large artery atherosclerosis Cholesterol plaque ↓ diameter of intra- or extracranial vessel Cardiac embolism Blood clot in heart breaks free, travels to brain Other E.g. volume loss, severe infection Unknown E.g. 2 or more mechanisms Modest ↓ in O2 at penumbra (see figure) Authors: Mizuki Lopez Andrea Kuczynski Illustrator: Mizuki Lopez Reviewers: Sina Marzoughi Usama Malik Hannah Mathew Ran (Marissa) Zhang Andrew M Demchuk* Gary M. Klein* * MD at time of publication Significant ↓ in O2 at ischemic core (see figure) ↑ Anaerobic metabolism ↓ ATP Production Dysfunction of Na+/K+ ATPase pump (for 1 ATP molecule, 3 Na+ moved out of cell, 2 K+ moved into cell) H2O influx following Na+ Cerebral edema Compression of vessels and surrounding tissue damages blood-brain barrier ↑ Permeability of damaged blood-brain barrier Infiltration by peripheral immune cells Immune cells release inflammatory cytokines ↓ Cerebral Blood Flow Penumbra Ischemic core Metabolic demands are greater than supply of ATP Cell death Microglia (resident neural immune cells) activate to clean dead cell debris Microglia release inflammatory cytokines (TNFα, IFγ, IL-1β) Cytokines lead to astrocyte activation (support cells for neurons) Astrocytes release more inflammatory cytokines Inflammation of brain tissue ↑ Na+, Ca2+ influx, K+ outflux ↓ Glutamate (excitatory neurotransmitter) reuptake by astrocytes (support cells for neurons) ↑ Glutamate in extracellular fluid Spreading depolarization from core (unclear mechanism) Activate biochemical pathways including glutamate receptor activation ↑ Glutamate activity Activate glutamate receptors that conduct Ca2+ ↑ Ca2+ influx into neuron Activation of catabolic proteases, lipases, nucleases in neuron Dysfunction of neuronal protein synthesis and activity Neuronal cell death ↑ Volume of dead (infarcted) brain tissue Neurons depolarize and release glutamate Reversal of Na+ Dependent Glutamate Reuptake Transporters on astrocytes (normally 3 Na++ 1 H+ + 1 glutamate into cell, for 2 K+ out) ↑ Glutamate in extracellular fluid Stroke symptoms (e.g. weakness, slurred speech, visual field losses, autonomic dysfunction) (see Ischemic Stroke: Impairment by Localization stroke slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 14, 2017; updated November 6, 2022 on www.thecalgaryguide.com

Cirrhosis

Cirrhosis: pathogenesis and complications Author: Chunpeng Nie Yan Yu Reviewers: Paul Ratti, Amy Maghera, Vina Fan, Ben Campbell, Sam Lee*, Mayur Brahmania* *MD at time of publication Chronic viral hepatitis (B, C, or D) Hepatitis D occurs with hepatitis B Alcohol related liver disease Non-alcoholic steatohepatitis Autoimmune: autoimmune hepatitis, primary biliary & sclerosing cholangitis Genetic: hemochromatosis, Wilson’s disease, α1- antitrypsin deficiency Toxic: drugs may rarely cause chronic liver disease or cirrhosis Severe or chronic hepatocyte injury overrides regenerative capacity → Fibrosis Cirrhosis Mild fibrosis may reverse with treatment of underlying cause Nodular/shrunken liver on ultrasound ↑ Liver stiffness on transient elastography Diffuse fibrosis with nodular regeneration on biopsy Fibrotic liver provides ↑ resistance to blood flow Portal hypertension Irreversible formation of fibrosis, within which hepatic cell regeneration is restricted to form nodules of poorly-functioning cells Inflammation → epigenetic changes, oncogene mutations Hepatocellular carcinoma ↑ Serum α-fetoprotein (sensitivity 50%, specificity 99%) Fibrosis disrupts normal function of hepatic lobules Hepatic insufficiency ↓ Liver synthetic function ↓ Thrombopoietin synthesis Thrombocytopenia ↓ Conjugation of bilirubin, ↓ secretion of bilirubin into bile ducts, and ↓ drainage of bilirubin into hepatic duct Accumulation of serum bilirubin >30 μmol/L Jaundice Scleral icterus, jaundiced frenulum ↑ Pressure in portal venous circulation Portosystemic shunts Increased flow to esophageal, rectal, and splenic veins Vascular stretch → endothelial vasodilator (e.g. NO) release Vasodilators enter systemic circulation Pulmonary vasodilation Blood cells in pulmonary vasculature have ↓ time for gas exchange Hepatopulmonary syndrome (rare) Dyspnea or hypoxemia, worsened when upright ↓ Synthesis of clotting factors (V, VII, IX, X, XI, XII, fibrinogen, prothrombin) and anticoagulant proteins (antithrombin, proteins C/S) Unpredictable imbalance of hemostatic and anticoagulant factors Elevated INR ± coagulopathy Impaired metabolism of waste products and toxins Toxins (mainly ammonia) accumulate and cross the blood- brain barrier Hepatic encephalopathy Day-night reversal, asterixis, delirium Varices (dilated veins in the esophagus, stomach, or rectum) Variceal bleed GI bleed and hypovolemia Backflow of blood into spleen Splenomegaly Enlarged spleen sequesters (traps) blood cells Cytopenias (eg. thrombocytopenia or anemia), petechiae, easy bruising ↓ Blood flow to kidneys, which sense ↓ effective blood volume Kidneys retain water and Na+ ↑ Hydrostatic pressure in splanchnic vessels ↓ Albumin synthesis ↓ Capillary oncotic pressure Net fluid flux out of vasculature into interstitial space Ascites (fluid in peritoneal cavity) Peripheral edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 7, 2022, updated November 6, 2022 on www.thecalgaryguide.com

Hidradenitis Suppurativa

Genetic mutations causing impaired function of gamma-secretase (NCSTN, PSEN1 or PSENEN genes) Defective notch signaling pathway (a regulator of many cell processes) Hormones (excess androgen activity) Smoking (nicotine exposure) Skin to skin friction Systemic inflammation Hidradenitis Suppurativa: Pathogenesis and Clinical Findings Other unknown genetic factors Follicular occlusion HS nodule Epidermal layer Dermal- Epidermal Junction Dermal layer Inflammatory cytokine- mediated activation of nociceptors Inflammatory cytokines Sebaceous gland Apocrine sweat gland Hair follicle Pilosebaceous- apocrine unit Changes in gene expression of hair follicle and apocrine gland anti-microbial peptides Accumulation of corneocytes (dead keratinocytes) and sebum àfollicular occlusion and rupture ↑ Interleukin-36 (IL-36, a cytokine) Altered keratinocyte differentiation Hair follicle hyperkeratinization Abnormal structure and function of the pilosebaceous- apocrine unit Infiltration of normal skin flora microbes, macrophages, dendritic cells, and Th17 cells Increased density of nicotinic acetylcholine receptors in pilosebaceous-apocrine unit (see figure) Mechanism not fully understood Hyperhidrosis Pain Innate immune cells produce inflammatory cytokines: tumour necrosis factor alpha (TNF-α) and various interleukins (IL-1, IL-6, IL-12, IL-17, IL-22 and IL-23) IL-17 promotes neutrophil migration into the skin Formation of neutrophil extracellular traps (NETs) B-cell activation and IgG autoantibody formation against skin tissue antigens Scarring Ongoing inflammation impairs wound healing Granulocyte infiltration and activation, release of granulocyte colony-stimulating factor Accumulation of keratin, purulent and/or serosanguinous fluid in dermis Inflammatory papules, nodules, and abscesses Pro-inflammatory cytokine-mediated response, leading to epithelial hyperplasia with increased fibrosis and collagen remodelling in the dermis Formation of epithelial tissue tunnels in the dermis with two cavities on either end that open to the skin surface and fill with fluid or keratin Hidradenitis Suppurativa Chronic Inflammatory skin disease that occurs in areas with a high density of apocrine sweat glands, including the axilla, underneath the breasts, groin, and buttocks Sinus tracts (dermal connections between lesions) Double-ended comedones Authors: Leah Johnston Reviewers: Mehul Gupta Lauren Lee Stephen Williams Ben Campbell Laurie Parsons* * MD at time of publication Wound drainage and odour Psychological distress Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 30, 2023 on www.thecalgaryguide.com

Inhalational Injury

Inhalation Injury: Pathogenesis and complications Authors: Marshall Thibedeau, W Fraser Hill, Paloma Arteaga Juarez Reviewers: Spencer Yakaback, Tony Gu, Dami Omotajo, Ben Campbell, Yan Yu*, Michael Liss*, Duncan Nickerson*, Donald McPhalen* * MD at time of publication Smoke Inhalation Suspect if patient found unconscious, history of fire in a confined space and presence of facial burns Convective heat transfer Exposure to chemical irritants Tracheobronchial injury Injury stimulates vasomotor and sensory nerves of the trachea and bronchi Neuropeptides from neurons are released into local circulation and activate nitric oxide Inhalation of toxins Lack of O2 in an enclosed space Asphyxiation (O2 deprivation in lungs) Acute hypoxemia Loss of consciousness Death Upper airway injury (above vocal cords) Cell lysis & necrosis Local release of inflammatory substances ↑ Vascular permeability à edema of tissues in upper airway Damage to lower respiratory tract cilia ↓ Mucus clearance from alveoli Parenchymal injury (delayed reaction dependent on severity of burn) Alveolar epithelial and endothelial barrier irritation/damage Inflammatory response Carbon monoxide poisoning Cyanide poisoning Cyanide binds to mitochondrial cytochrome oxidase a3 CO binds more strongly to hemoglobin than O2 ↑ Carboxyhemoglobin in blood, ↓ free hemoglobin available to bind O2 in the lungs ↑ Affinity for O2 on remaining binding sites in hemoglobin (i.e. hemoglobin binds O2 more strongly and is slow to release it) ↓ O2 delivered to tissues Inhibition of cytochrome c oxidase Mucous obstructs airways Air retained distal to the obstruction is resorbed from nonventilated alveoli Regions without gas collapse i.e atelectasis ↑ Risk of infection ↓ Mitochondrial respiratory chain function Impaired oxidative phosphorylation & cellular energy production Cellular dysfunction in high metabolic tissues Nitric oxide acts as a vasodilator in alveolar arterioles Loss of hypoxic vasoconstriction (constriction of arterioles in alveoli due to ↓ O2) Reactive inflammation & bronchoconstriction Stridor Complete airway obstruction ↑ Vascular permeability leading to fluid leakage into interstitium and alveoli Blood flow to poorly ventilated alveoli is maintained Ventilation/perfusion (V/Q) mismatch (regions of lung not effectively ventilated despite being well perfused by blood) Acute Respiratory Distress Syndrome See ARDS Pathogenesis slide Hypoxemia Lower airway edema Wheezing Coughing Impaired brain function Muscle weakness Impaired heart function Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published November 10, 2019; Updated on February 12, 2023 on www.thecalgaryguide.com

Central Retinal Vein Occlusion

Central Retinal Vein Occlusion: Pathogenesis and clinical findings Authors: Graeme Prosperi-Porta Mina Mina Reviewers: Stephanie Cote Usama Malik Mao Ding Johnathan Wong* *MD at time of publication Hypercoagulable state (pathologic state where there is an exaggerated tendency for the blood to clot) ↓ Anticoagulation (e.g., Protein C or S def) and/or ↑ coagulation (e.g., malignancy, Polycythemia Vera) Non-ischemic (perfused) CRVO Glaucoma (a disease characterized by ↑ intraocular pressure) Optic disc drusen (calcified nodules located within the optic disk – the most anterior part of the optic nerve) Diabetes Dyslipidemia Hypertension Vasculitis (inflammation of blood vessels; e.g., sarcoid, Systemic Lupus Erythematosus) Endothelial damage Pupillary responses do not vary between both eyes when a light is shone in one eye at a time Relative afferent pupillary defect (RAPD) mild or absent Lost vascular wall integrity Normal retinal electrical response to a light stimuli Normal electro- retinography (ERG) with b- wave >60% Few scattered Intra-retinal hemorrhages ↓ In retinal electrical response to a light stimuli Pupils respond differently to a light stimulus shone in one eye at a time Severe ↓ in visual acuity (Snellen acuity of <20/400) Visual field deficits ↓ b-wave amplitude (<60%) on ERG RAPD present ↑ Pressure compromises retinal vein outflow Central retinal atherosclerosis (build-up of fat & cholesterol plaque in arteries) & hardening Atherosclerotic changes in the central retinal artery compress the central retinal vein (since they are both held together in region of the optic disc) Venous stasis (stagnation of blood flow) ↑ Likelihood of thrombus formation Central Retinal Vein Occlusion (CRVO) A common retinal vascular disease characterized by blockage of the main vein that drains blood from the retina CRVO classified based on the degree of perfusion (as seen through retinal angiography) Ischemic (nonperfused) CRVO ↑ Intraluminal venous pressure Dilated tortuous retinal veins Normal visual fields Vascular wall integrity lost Four-quadrant hemorrhages described as “blood and thunder” on fundus exam Obstruction due to thrombus ↓ Retinal capillary perfusion causes ischemia Hypoxia in the retinal tissues ↑ Release of vascular endothelial growth factor to revascularize diseased tissue & overcome hypoxic conditions Angiogenesis (formation of new blood vessels) Intraretinal infarcts “Cotton wool spots” on fundus exam Venous capillary fluid/protein leakage Mild retina, macula and disc edema Moderate ↓in visual acuity often (Snellen acuity >20/400) New vessel proliferation can occur in the anterior chamber of the eye This change can block the outflow path of the aqueous humor in the eye Neovascular glaucoma Neovascular vessels are structurally different in comparison to regular retinal vasculature Neovascular vessels are more fragile ↑ Likelihood of rupture Vitreous hemorrhage Neovascular vessels lack tight junctions ↑ Fluid leakage Retina, macula and disc edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First Published June 28, 2017, updated March 4, 2023 on www.thecalgaryguide.com

Pyogenic Brain Abscess on MRI

Pyogenic Brain Abscess on MRI: Findings and Pathogenesis Common pathogens such as staphylococcus and streptococcus bacteria exist in the outside environment or on the skin Hematogenous Spread Direct Spread Pathogen travels to brain by bloodstream Pathogen travels to brain by ears or sinus Pathogen enters the brain parenchyma by crossing the blood brain barrier (BBB) transcellularly, paracellularly or by a Trojan Horse mechanism Authors: Omer Mansoor, Aly Valji, Nameerah Wajahat Reviewers: Mao Ding, Reshma Sirajee, James Scott* *MD at time of publication R Transcellular Pathogen invades BBB cell directly to enter Paracellular Pathogen goes between BBB cells by disrupting tight junctions Trojan Horse Pathogen bypasses BBB by hiding inside a macrophage cell Ring Enhancing Lesion Sensitive, but not specific for a Brain Abscess Pathogen causes parenchymal inflammation and progresses through four stages of infection Axial T1 + Gadolinium MRI Head. Pyogenic Brain Abscess showing infection at Stage 3 or 4. T1 highlights fat, whereas T2 highlights fat and water*. R Stage 1: Early Cerebritis Focal infection (2-3 days) with no pus formation Stage 2: Late Cerebritis Progressive (1 week) infection of abscess Stage 3: Early Encapsulation In 1-2 weeks, pus is formed from the pathogen Stage 4: Late Encapsulation After 2 weeks, abscess shrinks in size as it necroses Pathogen causes acute inflammatory changes of swelling (edema) and vascular congestion No fibrous capsule is formed yet and infection is not well localized on a T1 MRI Increased edema could be seen on T2 MRI Poor Demarcation and Vasogenic Edema Abscess is not well-defined with minimal enhancement on T1 but can have increased signal on T2 Fibrous capsule is formed by surrounding healthy brain tissue that walls off abscess Capsule is made of granulation tissue and fat, which lights up non-specifically on a T1 MRI Use Diffusion Weighted Imaging (DWI) to distinguish abscess from other brain lesions DWI measures water diffusion in different directions, specifically diseased areas where water movement is restricted Restricted Diffusion Edema and inflammation allow water to move freely (hyperintense signal) *Imaging Source: Feraco et al., 2020: https://jptcp.com/index.php/jptcp/article/download/688/685?inline=1 DWI Sequence Axial MRI Head. Same Pyogenic Brain Abscess as above. DWI is the mainstay imaging sequence for diagnosing a pyogenic brain abscess*. Legend: Pathophysiology Mechanism Radiographic Findings Complications Published Mar 25, 2023 on www.thecalgaryguide.com

Acute Pulmonary Embolism on CTPA

Acute Pulmonary Embolism: Computed Tomography Pulmonary Angiogram (CTPA/CTPE) Virchow’s Triad: Hypercoagulability, venous stasis, vascular endothelial injury Image Source: European Society of Radiology Image: Polo mint sign on axial CTPA. Image Source: Journal of The Indian Academy of Echocardiography Image: Railway sign on axial CTPA. Image Source: Moore et al. 2018 Image: Pleural effusion and pulmonary infarction on axial CTPA. Authors: Aly Valji, Nameerah Wajahat, Omer Mansoor Reviewers: Reshma Sirajee, Sravya Kakumanu, Victória Silva, Mao Ding Vincent Dinculescu* *MD at time of publication Deep Vein Thrombosis (DVT): Majority of pulmonary embolism (PE) arise from DVT: Clot travels via inferior vena cava → right atrium → right ventricle → pulmonary arteries/arterioles See “Virchow’s Triad and Deep Vein Thrombosis” for full pathogenesis Polo Mint Sign Clot visualized in short axis, Filling defect entirely surrounded by IV contrast creating a circle (polo mint) Railway Sign Clot visualized in long axis, Filling defect surrounded by IV contrast on two sides creating the appearance of a railway track Type I or II Ventilation/Perfusion respiratory failure (V/Q) mismatch Reverse Halo Sign Pulmonary infarction leads to wedge shaped opacity with a rim of consolidation (black arrows) surrounding “ground glass” (red arrows) Pulmonary Embolism: Clot in pulmonary arteries See “Signs and Symptoms of Pulmonary Embolism” for full presentation Saddle Embolus: Large clot over the pulmonary trunk bifurcation Lobar/Segmental/Subsegmental Embolus: Clot within the pulmonary arteries of the lungs Blockage of pulmonary arteries = ↓ Blood flow, ↑ Right heart pressure ↓ Gas exchange b/w lungs and blood Ischemia of lung tissue → infarction → inflammation of dead tissue ↑ Right heart filling and expansion Left heart filling impaired ↓ Cardiac output due to ↓ Left heart filling “Massive PE” = sustained systemic hypotension or bradycardia (SBP < 90 mmhg, HR < 40 bpm) Saddle Embolus Filling defect due to blockage of bifurcation. IV contrast appears white, and embolus appears grey Pleural Effusion Exudative Pleural Effusion Tissue inflammation → ↑ blood vessel permeability = Leakage of fluid into pleural space Transudative Pleural Effusion ↑ Hydrostatic pressure from right heart congestion = Pushes fluid into pleural space Image Source: Samra et al. 2017 Image: Saddle embolus on axial CTPA. Legend: Pathophysiology Mechanism Radiographic Findings Complications Published March 28, 2023 on www.thecalgaryguide.com

Coronary Artery Bypass Graft CABG Indications

Coronary Artery Bypass Graft (CABG): Indications Author: Breanne Gordulic Reviewers: Miranda Schmidt Ben Campbell Sunawer Aujla Angela Kealey* * MD at time of publication Symptomatic multivessel (≥ 3 vessels) coronary artery disease (MVCAD) or complex MVCAD Acute coronary syndrome (ACS) Left main coronary artery disease Multivessel (≥ 3 vessels) CAD and diabetes Cardiac surgery required for other pathology Multivessel CAD, LV dysfunction and congestive heart failure (CHF) Complex CAD includes stenosed vein grafts, bifurcation lesions, calcified lesions, total occlusions, ostial lesions STEMI initial treatment is PCI/thrombolysis CABG outcomes compared to percutaneous coronary intervention (PCI) in MVCAD include ↑ survival in diabetes, ↑ survival with LV dysfunction, ↓ repeat revascularization, ↓ myocardial infarction, ↓ stroke ↑ Risk of failure in complex CAD with PCI Rapid reperfusion to myocardium most important in STEMI to decrease myocardial damage CABG can be considered for residual stenoses 6-8 weeks later NSTEMI or unstable angina (UA) with MVCAD involving at least three vessels including the proximal left anterior descending (LAD) Left main coronary artery divides into left anterior descending (LAD) and left circumflex (LCx) which supplies 2/3 of myocardium ↑ Survival Myocardial infarction from left main artery occlusion Death Left main stenosis Ventricular dysrhythmias Ongoing ischemia LV dysfunction Hemodynamic instability ↑ risk of PCI CABG has mortality benefit ↓ Number of operations ↑ Risk of cardiovascular disease in diabetes Revascularization indicated along with other cardiac surgery Multivessel CAD with >90% stenosis and CHF LV ejection fraction <35% ↑ Risk of atherosclerosis from hyperglycemia and dyslipidemia CABG bypasses several atherosclerotic plaques in coronary arteries ↑ Durability ↑ Complete perfusion Valve stenosis or regurgitation Septal defect Aortic root or arch pathology Combination procedure Evidence of ischemia at rest Evidence of impaired LV function at rest ↓ All-cause mortality in CABG vs medical management Chronic obstructive pulmonary disease Abbreviations: • ACS- acute coronary syndrome. Acute reduction in blood flow to heart muscle resulting in cell death. • CAD- coronary artery disease. Narrowing or blockage of the coronary arteries by plaque • NSTEMI- myocardial infarction (heart attack) with no ST elevation on electrocardiogram • PCI- percutaneous coronary intervention. A balloon tipped catheter is used to open blocked coronary arteries; a stent may be placed. • STEMI- myocardial infarction with ST segment elevation on electrocardiogram Consider revascularization (restore blood flow to blocked or narrowed blood vessels) of coronary arteries to increase perfusion to myocardium (heart muscle) Coronary artery bypass graft recommended Assess surgical risk and comorbidities with evaluation by heart team that includes both a cardiac surgeon and interventional cardiologist (SYNTAX Trial) Individual management plan for patients with comorbidities that increase mortality Frailty Chronic Renal Failure ↑ Inflammation and deregulated angiogenesis affects all organ systems ↓ Physiologic reserve and ↓ ability to recover from acute stress ↑ Pneumonia ↑ Respiratory and Renal Failure ↑ Stroke ↑ In hospital mortality ↓ Survival two years after surgery Use Society of Thoracic Surgeons Score, EuroSCORE, or SYNTAX II Score to predict patient outcome with anatomy, disease severity, and preoperative characteristics Coronary Artery Bypass Graft Surgery to take healthy blood vessels from the body and connect them proximally and distally to blocked coronary arteries Cardiopulmonary bypass, fluid overload, ↑ renal vasoconstriction and ↓ renal oxygenation from rewarming Kidney injury ↑ End stage kidney disease Blood flow restored to ischemic myocardium ↓ Angina ↑ Quality of life ↑ LV function ↑ Survival Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 12, 2023 on www.thecalgaryguide.com

OA Clinical findings

Osteoarthritis: Pathogenesis and clinical findings Ehlers-Danlos Syndromes (connective tissue disorders, e.g., Familial Hypermobility Syndromes) Damage of normal cartilage under abnormal loading Authors: Sean Spence Modhawi Alqanaie Reviewers: Yan Yu Jennifer Au Mao Ding Gary Morris* * MD at time of publication Single large traumatic event or repeated microtrauma Damage to normal articular cartilage under normal loading (force put on a joint) Genetic anomalies in cartilage production and inborn errors of cartilage metabolism Damage of abnormal cartilage under normal joint loading Destruction/attrition of articular cartilage Osteoarthritis A degenerative joint disease that can affect both load bearing joints (knee, hip) as well as in smaller joints (proximal inter-phalangeal, carpometacarpal joints in hand) Repeated physical joint trauma Aberrant bone deposition secondary to wear on subchondral bone Formation of osteophytes (bony projections) and subchondral sclerosis (bone thickening) Lack of cartilage Direct contact between bony processes with movement of the joint Inflammation alters the chemical milieu of joint tissue Synovial fluid forced into bone Damage to subchondral (under cartilage) blood vessels Subchondral fractures cytokines regulate hyaluronic acid synthase Synovium makes lower molecular weight hyaluronic acids (a potent proinflammatory molecule) ↓ synovial fluid viscosity ↑ risk of infection Increased secretion of proteolytic enzymes ↑ joint fluid production Joint effusion Disruption of normal joint architecture Palpable bony hypertrophy (ex. Bouchard’s nodes (bony bumps on the middle joints of the finger)) Impaction of osteophyte with normal joint structures during movement Physical disability Crepitus (grating sound in a joint) Joint movement with reduced lubrication stimulates joint nociceptors Stimulation of joint nociceptors (sensory receptors that detect damaging stimuli) in subchondral bone Pain with use of joint Pain with motion ↓ Range of motion Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 1, 2012, updated May 18, 2023 on www.thecalgaryguide.com

diverticulosis-vs-diverticulitis-distinguishing-features

Diverticulosis vs. Diverticulitis: Distinguishing features Authors: Sahil Prabhnoor Sidhu, Vadim Iablokov, Vina Fan Reviewers: Brandon Hisey, Laura Byford-Richardson, Raafi Ali Dr. Sylvain Coderre* * MD at time of publication Local inflammation Diverticulitis Inflammation of diverticuli Conditions causing inherent weakness in bowel wall, i.e. aging, Ehlers-Danlos syndrome, Marfan syndrome Risk factors (i.e. low fiber diet, obesity, inactivity, smoking) contributing to reduced gut motility ↑Intraluminal pressure in the colon Herniation of colonic mucosa and submucosa through circular muscle at points of weakness to form outpouchings Diverticulosis Presence of outpouchings in the colon (diverticuli) Note: In Western populations, most diverticulosis is left-sided, whereas in Asian populations, these outpouchings are more often right-sided. Mucosal abrasion or micro-perforation by ↑ intraluminal pressure or dense food particles Bacterial overgrowth, dysbiosis and passage into the lamina propria Feces collects in diverticuli Gut bacteria metabolize undigested material and produce gas Stretching of colon Bloating wall irritates and visceral afferent flatulence nerves Episodic abdominal discomfort and cramping Blood vessels in the mucosa and submucosa (vasa recta) are stretched over the diverticuli, and may rupture from ↑ pressure Diverticular bleed Painless hematochezia (passage of fresh blood from the rectum) Inflammatory cytokines activate clotting factors Clotting of blood in vessels supplying diverticula Inflammatory cytokine release (IL-6, TNF-α) Cytokines enter systemic circulation Edema in the bowel wall Irritation of adjacent parietal peritoneum and somatic nerves Left lower quadrant (LLQ) pain, guarding Small abrasions are walled off by pericolic fat and mesentery ↑WBC Fever Inflammation may spread to nearby organs, leading to ulceration and abnormal connections between organs Pericolic abscess No hematochezia Local ischemia and focal necrosis resulting in loss of integrity of the bowel wall Perforation Generalized peritonitis Colonic obstruction (rare) Fistulae (rare): i.e. colovesical, coloenteric Stricture/fibros is formation with healing Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 12, 2016; Updated July 30, 2023 on www.thecalgaryguide.com

Knee Osteoarthritis

Authors: Jared Topham Knee Osteoarthritis: Pathogenesis and clinical findings Reviewers: Liam Thompson, Raafi Ali Yan Yu*, Kelley DeSouza* * MD at time of publication Primary Causes Secondary Causes Aging ↓ Synovial fluid in joint Gender Females > males Genetics Family history of osteoarthritis Race Black > Caucasian Joint malposition (e.g. valgus or varus) Articular trauma Inflammatory disease or infection (e.g. Rheumatoid or septic arthritis) Obesity and ↑leptin ↑ Chondrocytes, inflammatory mediators, and metalloproteinases Extracellular matrix degradation ↑ Knee joint loading forces Metabolic syndromes (e.g. diabetes mellitus) ↑ Oxidative stress and insulin resistance Low-grade systemic inflammation ↓ Elasticity and ↑ degradation of cartilage ↑ Friction in knee joint with movement ↓ Cartilage along femoral groove and posterior surface of patella Pain, catching, and crepitus (crackling/clicking sound) in the patellofemoral joint Inability/difficulty with kneeling or climbing stairs Abnormal distribution of forces accumulate and stress articular surface ↑ Damage/laxity to soft tissue structures stabilizing knee joint Knee Osteoarthritis (Multifactorial entity characterized by cartilage breakdown, deterioration of connective tissue, and bone deformities) ↓ Cartilage between distal femur and proximal tibia ↓ Joint spaceàto articular dysfunction Radiographic changes See Osteoarthritis (OA): X-Ray Features slide Repeated attempts to repair cartilage and joint disruption Subchondral bone thickening (sclerosis) under joint cartilage and bone spur (osteophyte) formation around joint line Rotational/antero-posterior instability and ↑ external adduction moments during walking Alterations in proteoglycans, fiber arrangement, and collagen composition in soft tissue structures within/around knee joint ↑ Shear forces and medial compartment narrowing erode and pinch soft tissue structures within the knee joint Cruciate ligament degeneration Weakened passive stabilizers of the knee joint Knee giving way and instability (falls) Meniscal tears, if large àprevents knee extension/flexion Locking of the knee Joint line tenderness: Patient points to area of tenderness/pain reproducible upon palpation Anatomical axis of hip, knee, and ankle joints ↑ loading medially Medial > lateral joint line tenderness ↑ Joint friction activating nociceptors in the surrounding anatomical tissues Injury and inflammation ↑ nociceptive responses in soft tissue structures and subchondral bone within knee joint Nociceptive feedback to brain inhibits activity of motor cortex neurons controlling muscles around the knee ↓ Motor output and muscle activation over time ↓ Muscle strength/endurance, lower limb muscle use, functional ability (walking, stairs, etc.) Joint inflammationà accumulation of fluid within joint Stiffness, swelling, redness, and pain Limited joint space reduces range of motion for femur to roll/slide on tibia ↓ Knee flexion and extension Flexion contracture and antalgic gait Reduced weight acceptance of the joint and surrounding muscles/tendons ↓ Mobility and physical dysfunction Muscular atrophy Reduced function of active stabilizers of the knee joint (quadriceps, adductors, hamstrings) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 30, 2023 on www.thecalgaryguide.com

Rotator Cuff Disease

Rotator Cuff Disease: Pathogenesis and clinical findings Authors: Jared Topham Reviewers: Raafi Ali, Yan Yu*, Kelley DeSouza* * MD at time of publication Aging Collagen fiber disorientation and myxoid degeneration Tendons, ligaments, and connective tissue are replaced by gelatinous and/or mucoid substance Obesity ↑ Loading on shoulder structures ↓ Static stability (from glenoid labrum and ligamentous components) of glenohumeral joint Tensile forces Repeated eccentric tension from overhead activities Trauma, sports, and occupation ↑ Torque, compression, and translational stresses Metabolic syndromes Reactive oxygen species interact with ↑ glucose forming advanced glycation end-products (AGEs) which accumulate in soft tissues Smoking Impingement syndromes Vessel damage, ischemia, tenocyte apoptosis Macro-trauma causing an acute, complete tear in the rotator cuff muscle(s) ↓Dynamic stability (from rotator cuff and periscapular muscles) and range of motion of the shoulder at the glenohumeral joint ↑ Bone on bone contact of proximal humeral head and boney structures of the scapula Subacromial bursa degeneration ↓ Protection of underlying supraspinatus muscle from attrition between humeral head and acromion Rotator Cuff Syndrome (Inflammation, impingement, or tearing of one or more of the four muscles/tendons of the rotator cuff: supraspinatus, subscapularis, infraspinatus, teres minor) Repetitive loading and micro-tearing of tendon/muscle fibers ↑ Oxidative stressors and inflammatory cascades ↓ Vascularity of rotator cuff structures Radiographic changes: See Rotator Cuff Disease: X-ray and ultrasound features slide, in addition to: calcific tendonitis, calcification of in the coracohumeral ligament, and hooked acromion (calcification from tendon pulling) In some cases, soft tissues enclose/surround shoulder joint capsule thicken (fibrose) and tighten Degenerative joint disease and rotator cuff arthropathy Proximal humeral head migration and ↓ subacromial space Inflammation and insufficient healing of rotator cuff structures, which may lead to: Supraspinatus (shoulder abduction) degeneration Pain, shoulder stiffness, ↓ active AND passive range of motion Adhesive Capsulitis (frozen shoulder) Infraspinatus and teres minor (external rotation) degeneration Rotator cuff tendons become inflamed and irritated as they rub against acromion Subacromial impingement Subscapularis (internal rotation) degeneration +Lift-off test: Inability to hold dorsum of the hand off lumbar spine while internally rotating shoulder ↓ Shoulder strength and muscular atrophy Pain with passive shoulder flexion beyond 90° Winging of the scapula during arm adduction +Empty-can test: Weakness and/or arm depression with resisted abduction with arm internally rotated in 90° +Drop-arm test: Inability to maintain shoulder in abducted position at 90° and/or adduct the arm in a controlled manner (resulting in ”dropping”) Weakness to resisted external rotation with elbow in 90° flexion, inability to keep arm externally rotated (infraspinatus) +Hornblower’s sign: decreased external rotation strength in arm abduction (suggests additional teres minor tear) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 30, 2023 on www.thecalgaryguide.com

Mitral Regurgitation Pathogenesis and clinical findings

Mitral Regurgitation: Pathogenesis and clinical findings Coronary Artery Disease Authors: Juliette Hall, Victoria Nkunu Reviewers: Raafi Ali, Jack Fu, Usama Malik, Sina Marzoughi, Jason Waechter* * MD at time of publication (Ischemic Heart Disease & Myocardial Infarction) Myocarditis Left ventricular dilation displaces papillary muscles Dilation of the Tethering of mitral valve annulus chordae tendineae ↑ Volume and pressure in left atrium ↑ Volume pushed back into left ventricle Dilated left ventricle Apical impulse on palpation and auscultation ↓ Forward flow of blood out of heart Blood backs up into pulmonary circulation ↑ Intravascular hydrostatic pressure in pulmonary vessels Fluid extravasates out of vessels and into the lungs Papillary muscle rupture Mitral valve leaflets flail Mitral valve prolapse Structurally abnormal valve Connective tissue disorders Weak valve leaflets Rheumatic heart disease Dilatation of the mitral valve annulus, inflammation of leaflets Infective endocarditis Vegetations form on valve leaflets Mitral Regurgitation Blood consistently flows backward throughout systole Holosystolic murmur, radiates to axilla, ↑ with afterload (e.g. making a fist) Backflow of blood from left ventricle to left atrium due to impaired mitral valve closure S3 heart sound Myocardial remodeling ↓ Muscle efficiency ↓ Left ventricle systolic function ↓ O2 saturation, tachypnea, wheeze, ↑ work of breathing, crackles, frothy sputum (if severe) Congestive heart failure ↓ Stroke volume ejected into aorta ↓ Cardiac output ↓ Organ perfusion ↓ O2 to kidney Activation of renin-angiotensin- aldosterone system ↑ Reabsorption of water by kidneys ↑ Intravascular hydrostatic pressure systemically Peripheral edema Injury to kidney parenchyma ↓ ability for kidney to clear creatinine ↑ Serum creatinine Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 3, 2018, updated Oct 15, 2023 on www.thecalgaryguide.com

Death Cardiovascular Respiratory and Neurologic Mechanisms

Death: Cardiovascular, Respiratory and Neurologic Mechanisms Mitochondria in tissues unable to utilize O2 Reduced hemoglobin in blood to carry O2 Low oxygen content in blood (CaO2) Hypoxemia (Type I Respiratory Failure): low dissolved oxygen in blood (PaO2) Lungs can’t oxygenate blood fast enough Lungs can’t rid blood of CO2 fast enough Hypercapnia / hypercarbia (Type II Respiratory Failure): elevated dissolved CO2 in blood (PaCO2) Cerebral vasodilation Toxins: e.g. cyanide, pesticides, arsenic Severe anemia Distributive problems: Systemic inflammation (sepsis, anaphylaxis, pancreatitis), adrenal insufficiency, vasodilatory drugs Obstructive problems: Cardiac tamponade*, tension pneumothorax* or massive pulmonary embolism* Hypovolemic* problems (low blood volume): Hemorrhage, dehydration, widespread skin disruption or burns Cardiac valve dysfunction Myocardial infarction* or cardiomyopathy Cardiac arrhythmia or heart block Disturbed electrical activity in cardiomyocytes Peripheral metabolic disturbances Hypokalemia*, Hyperkalemia* Acidosis* (including renal failure) Hypothermia* Toxins* (e.g. cocaine, beta blockers, tricyclics) Severe thyroid derangement Inappropriate systemic vasodilation Adjacent forces impair heart filling Low cardiac preload Low stroke volume (SV; depends on valves, contractility, preload) Decreased systemic vascular resistance (SVR) Low blood pressure (BP = CO x SVR) Decreased cardiac output (CO = SV x HR) Disseminated intravascular coagulationàwidespread thrombi that occlude blood flow (also causes hemorrhage, see relevant box at left) Methemoglobinemia: some hemoglobin gets stuck in a state that can’t carry O2 Hemoglobin has reduced capacity to carry or release O2 Drugs: e.g. dapsone, nitrates Carbon monoxide poisoning Circulatory collapse / shock: inadequate perfusion of tissue with blood Respiratory collapse: blood has insufficient useable O2 content Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) Hypoxia*: inadequate O2 delivery or utilization in tissues Hypoxia creates metabolic disturbances that impair cardiac cells. Alternatively, any of the preceding conditions marked with (*) can directly trigger cardiac arrest first Pulseless Electrical Activity (PEA): organized activity on ECG with no cardiac output (can be preceded or mimicked by pseudo-PEA, in which there is still some output on ultrasound) Low atmospheric pressure or oxygen content Severe lung disease Asthma, COPD, interstitial lung disease, congestive heart failure, pulmonary hypertension, pulmonary embolism, lung collapse / atelectasis Acute respiratory distress syndrome Pneumonia, aspiration pneumonitis, inhalational injury, systemic inflammation, drowning Severe hypoventilation Respiratory fatigue, advanced COPD, chest wall disorders, neuromuscular disorders, upper airway obstruction, toxins (e.g. opioids, botulism) Can degenerate at any time Asystole: no cardiac electrical activity or output Death Respiratory arrest: cessation of breathing Inability to protect airway Decreased level of consciousness Note This is a broad overview of the many scenarios that can result in death. For detailed explanations of the various disease mechanisms, refer to the corresponding slides. * = reversible causes of cardiac arrest (Hs and Ts) Author: Ben Campbell Reviewers: Yan Yu* Huma Ali* * MD at time of publication Bradycardia (low heart rate, HR) Unopposed parasympathetic stimulation of heart (can also cause vasodilation, see Distributive problems) Disruption of spinal cord sympathetic control Injury to cervical or upper thoracic spinal cord Irreversible cessation of cardiac, respiratory, and brain function Prolonged seizure initially causes increased cardiovascular activity, until the system fatigues Disruption of respiratory control center in medulla Expanding skull contents squeeze brainstem (herniation) Increased intracranial pressure Edema from intracranial hemorrhage, trauma, brain mass Edema, inflammation, hypoxia and/or metabolic derangements cause diffuse neuron dysfunction Central nervous system infection Dementia, particularly with delirium Massive ischemic stroke Seizure activity prevents or alters breathing Metabolic disturbances that affect the central nervous system Hypoglycemia Hypocalcemia, hypercalcemia Hyponatremia, hypernatremia Uremia Acute liver failure (hyperNH4) Many drugs / toxins Withdrawal (e.g. EtOH) Status epilepticus Brainstem lesion (e.g. stroke, neoplasm, inflammatory) Nervous System Insult Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 11, 2023 on www.thecalgaryguide.com Respiratory System Insult Cardiovascular System Insult Cardiogenic problems

Non-Alcoholic Fatty Liver Disease

Non-Alcoholic Fatty Liver Disease: Pathogenesis and clinical findings Diagnosis of Metabolic Syndrome when ≥ 3 out of the 5 preceding risk factors are present Authors: Stephanie Happ Reviewers: Obesity Hypertension Diabetes Hypertriglyceridemia Hypercholesterolemia Iffat Naeem Sunawer Aujla Edwin Cheng* * MD at time of publication Insulin resistance develops in adipose tissue and hepatocytes ↓ Ability of insulin to suppress lipolysis of adipose tissue ↑ Delivery of free fatty acids from adipocytes to the liver ↑ De-novo lipogenesis in the liver Hepatic Steatosis: accumulation of fat in the liver (in the absence of alcohol consumption, termed Non-Alcoholic Fatty Liver (NAFL)) Steatohepatitis: chronic inflammatory and apoptotic climate in the hepatocytes (in the absence of alcohol consumption, termed Non-Alcoholic Steatohepatitis (NASH)) Fibrosis of the Liver: excessive scarring of liver tissue resulting from chronic inflammation, although liver architecture is largely intact Fat droplets form and grow in the hepatocytes Hepatic mitochondria increase their workload in attempt to break down the excess free fatty acids through beta-oxidation ↑ in cellular workload creates more reactive oxygen speciesà Inflammation and apoptosis of hepatocytes On-going inflammation damages hepatic stellate cells (the primary extracellular matrix–producing cells of the liver) causing the release of fibrinogenic cytokines Cirrhosis of the liver: normal lobular structure distorts and is replaced by regenerating nodules and bridging septa, disrupting normal liver blood flow Deposition of fibrotic material and collagen within the perisinusoidal spaces of the liver Decompensated Cirrhosis Hepatocellular carcinoma Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 25, 2023 on www.thecalgaryguide.com

RICE mechanism of action

Rest, Ice, Compression, Elevation (RICE): Mechanism of action Healing of an injury requires pain and inflammatory control to encourage activity. The goal of Rest, Ice, Compression, Elevation (RICE) is to decrease inflammation. Though activity itself will contribute to pain and inflammation, it is integral to the rehabilitation process. Authors: Matthew Roberts Emma Windfeld Reviewers: Alexander Arnold Amanda Eslinger Shyla Bharadia Mao Ding Bradley Jacobs* * MD at time of publication Rest: (weight bearing or stressful motion discontinued) Further damage to affected tissues from mechanical stress is prevented Ice: (applied to injury) Compression: (wrap applied to injured area) Mechanical force applied to tissue Excess fluid is pushed back into capillaries and lymph network Elevation: (limb raised above heart) Blood flow to tissue is constricted Mechanism not well understood ↓ delivery of inflammatory mediators such as polymorphonuclear neutrophils and macrophages to injured site ↓ production of inflammatory cytokines (pro-inflammatory substances) such as Tumor Necrosis Factor-α, Platelet Derived Growth Factor, Epidermal Growth Factor, and Transforming Growth Factor-β ↓ Inflammation Gravity ↑ venous blood return to systemic circulation ↓ edema (accumulation of fluid in interstitium) Early initiation of injury-specific rehabilitative exercises improves range of motion, strength, and proprioception Stress to targeted area induces inflammation that, when tightly regulated, is integral to repair Injured muscle, tendon, bone, or ligament is strengthened ↓ Pain ↑Range of motion and therefore function Early recovery from injury Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 9, 2013, updated Oct 15, 2023 on www.thecalgaryguide.com Rest, Ice, Compression, Elevation (RICE): Mechanism of action Healing of an injury requires pain and inflammatory control to encourage activity. The goal of Rest, Ice, Compression, Elevation (RICE) is to decrease inflammation. Though activity itself will contribute to pain and inflammation, it is integral to the rehabilitation process. Authors: Matthew Roberts Emma Windfeld Reviewers: Alexander Arnold Amanda Eslinger Shyla Bharadia Bradley Jacobs* * MD at time of publication Rest: (weight bearing or stressful motion discontinued) Further damage to affected tissues from mechanical stress is prevented Ice: (applied to injury) Compression: (wrap applied to injured area) Mechanical force applied to tissue Excess fluid is pushed back into capillaries and lymph network Elevation: (limb raised above heart) Gravity ↑ venous blood return to systemic circulation Blood flow to tissue is constricted ↓ delivery of inflammatory mediators such as polymorphonuclear neutrophils and macrophages to injured site Mechanism not well understood ↓ production of inflammatory cytokines (pro- inflammatory substances) such as Tumor Necorsis Factor-α, Platelet Derived Growth Factor, Epidermal Growth Factor, and Transforming Growth Factor-β ↓ Inflammation ↓ Pain ↓ edema (accumulation of fluid in interstitium) ↑Range of motion and therefore function Early initiation of injury- specific rehabilitative exercises improves range of motion, strength, and proprioception Stress to targeted area induces inflammation that, when tightly regulated, is integral to repair Injured muscle, tendon, bone, or ligament is strengthened Early recovery from injury Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications RICE: Mechanism of action Authors: Matthew Roberts Emma Windfeld Reviewers: Alexander Arnold Amanda Eslinger Shyla Bharadia Bradley Jacobs* * MD at time of publication Rest (weight bearing or stressful motion discontinued) Ice (applied to injury) Compression (wrap applied to injured area) Elevation (limb raised above heart) Constricts blood flow to tissue Mechanism not well understood Mechanical force applied to tissue ↓ Delivery of polymorphonuclear neutrophils and macrophages to injured site Excess fluid pushed back into capillaries and lymph network Gravity ↑ venous blood return to systemic circulation Prevents further damage to affected tissues from mechanical stress ↓ Production of inflammatory cytokines ↓ Edema (accumulation of fluid in interstitium) ↓ Inflammation ↓ Pain ↑Range of motion and therefore function Early initiation of injury-specific rehabilitative exercises to improve range of motion, strength, and proprioception Stress to targeted area induces inflammation that, when tightly regulated, is integral to repair Injured muscle, tendon, bone, or ligament is strengthened Early recovery from injury Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Aspiration Pneumonia

Aspiration Pneumonia: Pathogenesis and clinical findings Intractable vomiting ↑ Likelihood of oropharyngeal and gastric contents exiting the esophagus, entering the trachea to the lung If the acidic gastric contents are sterile, then aspirating this results in inflammation and lung injury without development of infection Aspiration pneumonitis Alveolar macrophages recruit neutrophils to local site of infection. Subsequent cytokine release compromises the vascular endothelial cell wall barrier and ↑ alveolar-capillary permeability ↑ inflammation due to fluid and cellular debris build-up in alveoli overdose (e.g. opioids) (e.g. stroke) Altered level of consciousness and impaired cough/clearance Tube Poor Alcohol and Substance Medications Neurologic diseases Esophageal and gastric motility disorders Impaired swallowing Chronic obstructive pulmonary disorder feeding oral health Bacteria adhere to epithelial surfaces and ↑ risk of airway and lung bacterial colonization Aspirated oropharyngeal and gastric contents can also contain bacteria ↓ Elimination and clearance of foreign bacteria from airway and lung Macroaspiration (large volume aspiration) of oropharyngeal bacteria, during eating and drinking Bacteria and fluid fill bronchi and alveolar space Aspiration Pneumonia Alterations to lung microbial flora An infectious lung process caused by inhalation of foreign bacterial and oropharyngeal and gastric contents Aspiration of acidic fluid and pneumonia causative pathogen (typically anaerobes or bacteria in normal oral flora) with resultant inflammation Infiltrate develops in a gravity-dependent pattern in patches around bronchi segments. Produces proinflammatory cytokines, (e.g. tumor necrosis factor-alpha, and interleukin-1) Hypothalamic production of prostaglandin E2 results in thermogenesis Fever Authors: Luiza Radu Reviewers: Mao Ding, *Yan Yu, *Jonathan Liu *MD at time of publication Aspiration to the right lung more common due to large diameter and more vertical orientation of the right main bronchus Crackles and ↑ lung vibrations (fremitus) on auscultation Productive Cough Impaired alveolar gas exchange Chemoreceptor detection of ↓ pO2 triggers ↑ ventilation Hypoxemia Dyspnea Consolidation in lower lobes (particularly superior segments) and posterior segments of upper lobes If untreated, a pus-filled lung cavity develops (e.g. abscess) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 11, 2024 on www.thecalgaryguide.com

Shoulder Impingement Syndrome

Shoulder Impingement Syndrome: Signs and Symptoms Calcific deposition Abnormal shoulder morphology Static subacromial narrowing Abnormal scapular rotation and tilt Scapular winging Weakness Degenerative changes to rotator cuff tendons Weakness Dynamic subacromial narrowing Repetitive overhead activity/shoulder overuse Muscle fatigue Repetitive compression forces on subacromial space Glenohumeral instability or stiffness Authors: Janelle Wai Dalal Awwad Reviewers: M. Patrick Pankow Reza Ojaghi Usama Malik Sunawer Aujla Ryan Shields* * MD at time of publication Internal/ Posterior Impingement Compression of rotator cuff tendons between humeral head and posterosuperior glenoid edge during end stage of throwing Pain with passive extension and lateral rotation + Posterior Internal Impingement Test Instability: Laxity of glenohumera l joint Stiffness: Scapular winging with downward tilt, shoulder protraction Primary/ Structural Impingement Any anatomical abnormalities Secondary/Functional Impingement Normal anatomy with motion abnormalities Impingement of underlying rotator cuff muscle-tendon unit and inflammation of subacromial bursa Rotator Cuff Syndrome External/ Subacromial Impingement Compression of subacromial bursa and rotator cuff (i.e. supraspinatus tendon) on the anterolateral acromion and coracoacromial ligament X-Ray: Normal Ultrasound: +/- Tendinopathy, muscle atrophy Pain with overhead movement Pain at night (e.g., sleep position, gravity) Pain with lifting (e.g., weight- training, groceries) Pain (between 60°-120°) with passive shoulder abduction + Painful arc Test Pain with passive shoulder flexion + Neer’s Test Pain with passive shoulder flexion (to 90°) + internal rotation + Hawkins-Kennedy test Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published May 27, 2018; updated Jan 11, 2024 on www.thecalgaryguide.com

Arachnoid Cysts MRI Findings

Arachnoid Cysts: Findings on MRI Imaging source: radiopaedia.org Authors: George S. Tadros Reviewers: Matthew Hobart, Shahab Marzoughi, James Scott* * MD at time of publication Extra-Axial Location Cyst is visualized outside of brain parenchyma Clear Demarcation Since the arachnoid cyst is bound by arachnoid membrane, it has well-defined margins CSF collection contained within a split arachnoid membrane that occurs during embryological development (primary) Cerebrospinal Fluid (CSF) collection within arachnoid membrane adhesions following trauma, infection, inflammation or surgery (secondary) Arachnoid cyst (fluid-filled sac) formation within the layers of the arachnoid membrane, outside of brain parenchyma (for full pathogenesis, see Calgary Guide slide Arachnoid Cysts: Pathogenesis and clinical findings) Use Diffusion Weighted Imaging (DWI) and Fluid-Attenuated Inversion Recovery (FLAIR) to distinguish from other cysts Isointense to CSF on T1 and T2 Arachnoid cyst contents should appear isointense to CSF on each MR sequence, including diffusion-weighted imaging Axial T2 MRI Head. Clearly demarcated hyperintense (bright) arachnoid cyst is seen (red arrows) Axial T1 MRI Head. Clearly demarcated hypointense (dark) arachnoid cyst is seen (red arrows) FLAIR allows for suppression of free water signal to enhance fluid with ↑ protein concentration Arachnoid cysts contain CSF-like fluid with very little to no protein Complete suppression on FLAIR Cysts are mostly fluid and contains no protein, so it is suppressed and appears darker in FLAIR images. Axial FLAIR MRI Head. Hypointense cyst is seen on FLAIR (red arrows), showing low protein content in CSF-like fluid inside arachnoid cyst DWI measures water diffusion in different directions and whether there is restriction on the direction of flow Fluid within the cyst can flow freely, with no restriction on the direction of movement Non-restricted diffusion There is no directional restriction on flow within the cyst (unrestricted diffusion), so it appears dark on DWI. Axial DWI MRI Head. Hypointense cyst is seen on DWI (red arrows), showing unrestricted diffusion within arachnoid cyst Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 20, 2024 on www.thecalgaryguide.com

Arachnoid Cysts Pathogenesis and clinical findings

Arachnoid Cysts: Pathogenesis and clinical findings Authors: George S. Tadros Reviewers: Yvette Ysabel Yao Shahab Marzoughi Gary Michael Klein* * MD at time of publication Failure in the embryological duplication or division of the arachnoid membrane Cerebrospinal fluid (CSF)-like fluid is trapped within the erroneous membrane Formation of a primary, congenital arachnoid cyst (most common cause) Head trauma, intracranial hemorrhage, or infection Inflammation and deposition of cellular matrix Adhesion of the arachnoid membrane CSF accumulates in the subarachnoid space (space between the arachnoid mater and pia mater) Formation of a secondary arachnoid cyst (less common) Cyst remains stable in size and does not expand (most common) Patients are asymptomatic Arachnoid cyst is diagnosed incidentally on unrelated neuroimaging (see Calgary Guide slide Arachnoid Cysts: Findings on MRI) Arachnoid Cyst Cyst grows in size and expands (rare but more common in children under four years of age) Cyst exerts pressure on other structures (mass effect) Suprasellar region Cyst ruptures into the subdural space (rare) CSF-like fluid accumulates in the subdural space Subdural hygroma (collection of non-bloody CSF) Intracranial hypertension (↑ intracranial pressure) Generalized symptoms Middle fossa Compression and irritation of the temporal cortex Seizures Focal symptoms depending on cyst location Cerebellopontine angle Compression of vestibulocochlear nerve (Cranial Nerve VIII) Compression and interruption of cochlear blood supply Cyst presses on the third ventricle and aqueduct buildup of CSF in the ventricles Obstructive hydrocephalus Cyst presses on the optic chiasm, hypothalamus, and pituitary Visual impairments and endocrinopathies Headache (most common) Vomiting Nausea Progressive hearing loss Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 25, 2024 on www.thecalgaryguide.com

Avascular Necrosis AVN of the Femoral Head Findings on MRI

Avascular Necrosis (AVN) of the Femoral Head: Findings on MRI Traumatic or atraumatic disruption of blood supply to the proximal femur (for full pathogenesis, see Calgary Guide slide Avascular Necrosis: Pathogenesis and clinical findings) Ischemia of the femoral head (usually unilateral for traumatic and bilateral for non-traumatic) Prolonged anoxia (total oxygen deprivation) within the femoral head Cell death (necrosis) of osteocytes and marrow cells in the femoral head, forming a focal lesion (sequestrum) Histiocytes and giant cells (immune cells) aggregate around the sequestrum, forming a “reactive zone” around the periphery of the sequestrum Apoptotic osteocytes in the anoxic reactive zone cannot be phagocytosed leading to dysregulated bone remodeling and osteosclerosis (hardening of bone and ↑ bone mineralization and density due to ↓ resorption and ↑ bone formation) Femoral head becomes progressively weaker while the mechanical load on it remains the same Progressive femoral head/subchondral bone collapse Osteoarthritis Areas with ↑ fluid content appear darker on T1w images Areas with ↑ fluid content appear brighter on T2w images Areas with ↑ bone density and ↓ fat content appear darker on T1w images Areas with ↑ bone density and ↓ fat content appear darker on T2w images Basic MRI Physiology Edema and inflammation increases fluid content Sclerotic areas have ↑ bone density and thus ↓ fat content Location of Signs Inflamed reactive zones are darker on T1w images Inflamed reactive zones are brighter on T2w images Sclerotic areas are darker on both T1w and T2w images Authors: George S. Tadros Reviewers: Matthew Hobart, Mao Ding Shahab Marzoughi David Cornell* * MD at time of publication T1w Signs on both T1-weighted and T2-weighted images are most commonly seen on the superior anterolateral aspect of the femoral head Single dark band on T1-weighted MRI A single band-like crescentic lesion of low signal intensity is seen on T1-weighted MRI images (white arrows). This band represents the edematous reactive zone between the necrotic and normal tissue, and typically extends to the subchondral plate Double Line Sign on T2-weighted fat-saturated MRI An outer distal low signal intensity line is seen (white arrows) representing reactive bone sclerosis Image source: radiologymasterclass T2w An inner proximal high signal intensity line is also seen (red arrows) representing vascular and repair tissue at the periphery of the sequestrum Image source: radiologymasterclass Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 27, 2024 on www.thecalgaryguide.com

Bacterial Infections from Transfusion

Bacterial Infections from Transfusion: Signs and Symptoms Caused by bacterial contamination of any blood product, most commonly platelets due to room-temperature storage Bacteria enters bloodstream directly through transfusion Immune cells (ex. macrophages, dendritic cells, monocytes, neutrophils) recognize bacteria Immune cells release pyrogens (either bacterial components or signalling molecules) upon recognition Pyrogens bind to receptors on the hypothalamus Hypothalamus ↑ body temperature set point Body generates and conserves heat to reach set point Immune cells release pro- inflammatory cytokines (messenger protein) Cytokines activate sympathetic nervous system via hypothalamus Adrenal glands release stress hormones (epinephrine and norepinephrine) into bloodstream Stress hormones bind to receptors on cardiomyocytes (heart muscle cells) ↑ Heart contractility ↑ Heart rate Cytokines circulate throughout the body Cytokines interact with endothelial cells of the blood vessels ↑ Nitric oxide production Relaxes smooth muscle cells of blood vessel walls Vasodilation (↑ blood vessel diameter) Hypotension Systemic inflammation Stimulate nerve endings in muscles Stimulate nerve endings in gastrointestinal tract’s lining Blood brain barrier’s integrity is compromised Nitric oxide reacts with oxygen to form reactive nitrogen species Tissue damage Fatigue Weakness Muscle aches Nausea and vomiting Immune and inflammatory cells enter the brain Authors: Arzina Jaffer Kayleigh Yang Reviewers: Nimaya De Silva Raafi Ali Michelle J. Chen Yan Yu* Kareem Jamani* * MD at time of publication Inflammation in the brain Activates pain processing centers in the brain Headache Damages neurons and disrupts cell communication Confusion and altered mental state Shivering Fever Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 30, 2024 on www.thecalgaryguide.com

Acute Otitis Externa Complications

Acute Otitis Externa (Swimmer’s Ear): Complications Acute Otitis Externa (AOE) Authors: Charmaine Szalay-Anderson Vaneeza Moosa Reviewers: Shayan Hemmati Shahab Marzoughi Ben Campbell Justin Lui* * MD at time of publication Spread to subcutaneous tissue Chronic otitis externa (>6 weeks) Chronic inflammation of the outer ear Fibroblast activation for collagen and extracellular matrix components production for tissue repair Excess accumulation of tissue Ear canal fibrosis (thickening) Ear canal stenosis (narrowing) Damage/obstruction to ear canal structures with impaired fluid drainage & pressure buildup Inflammation of the outer ear Recurrent or non-resolving acute otitis externa Dissemination of infection Spread to connective tissue and cartilage Perichondritis (inflammation of ear cartilage) Spread of Pseudomonas aeruginosa in an immunocompromised host or due to antibiotic resistance Rapid infectious spread through soft tissue to mastoid and/or temporal bone Malignant (necrotizing) otitis externa *can be life threatening Inflammation of connective tissue and bony structures Spread to tympanic membrane Myringitis (inflammation of tympanic membrane) Swelling and thinning of tissue Tympanic membrane perforation (tear) Immune reaction with inflammation Dead white blood cell, bacteria & tissue debris accumulation in the ear canal Pus formation with purulent otorrhea (discharge from ear) Localized pus accumulation Abscess Ear canal blockage Periauricular/ pinna (outer ear) cellulitis Facial cellulitis Erosion of temporal bone decreasing bony sound conduction Permanent conductive hearing loss Direct toxicity of pathogens to surrounding nerves Cranial nerve (CN) VII (facial) palsy (+/- CN X, XI, XII) Out-of- proportion primary otalgia (ear pain) Sensation of fullness in the ear Temporary hearing loss Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 4, 2022; updated Feb 7, 2024 on www.thecalgaryguide.com

Infective endocarditis

Infective Endocarditis: Pathogenesis, complications, and clinical findings Subacute Endocarditis Pre-existing valvular stenosis or regurgitation Non-laminar flow across valve damages valve endothelium A sterile thrombus forms Thrombus forms on the surface of a cardiac valve Acute Endocarditis Poor dental hygiene/recent dental procedure Invasive procedure/indwelling device Positive blood cultures Activation of immune system Valve Trauma Invading bacterium Intravenous (IV) drug use (mostly causes right sided endocarditis) Bacteria enter the bloodstream (bacteremia) In subacute cases, valvular abnormality usually present beforehand In all cases, vegetation forms on affected valve Immune complex deposit in kidney Immune complexes cause vasculitis in retinal vessels Immune complexes deposit subcutaneously ↓ Blood flow to organs perfused by the obstructed arteries Valve endothelium is damaged Bacteria adhere to thrombi on the cardiac valve endothelium Infective Endocarditis Infection of the thrombus typically produces a vegetation on the flow surface of a valve Immune complexes (complexes of antibody bound to antigen) form secondary to infection Generalized immune response Malaise Chills Fever (> 38°C) Author: Sean Spence George S. Tadros Reviewers: Yan Yu Jason Baserman Danny Guo Steve Vaughan* *MD at time of publication Parts of vegetation embolize systemically, obstructing arteries Infection destroys infected valve Smaller emboli block smaller vessels on hands/feet Microinfarctions Mitral regurgitation, Aortic stenosis, Aortic insufficiency (Valve involvement: Mitral > Aortic > Tricuspid) Vegetation seen on ultrasound/echocardiogram Damage to Glomerulonephritis glomeruli (Inflammation of glomeruli) Roth’s spots (retinal hemorrhages with pale centers due to coagulated fibrin) Osler nodes (tender, raised, red lesions found on the hands and feet) Organ infarction (tissue death) Splinter hemorrhages (small red streaks under nails) Janeway lesions (non-tender, red macules/nodules on palms/soles – only a few millimeters wide) Regurgitation (blood leaks back through the insufficient valve despite it being closed) Valve unable to fulfill normal functions (valve insufficiency) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 20, 2013, updated Feb 24, 2024 on www.thecalgaryguide.com

Onychomycosis

Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- compromised ↓ Immune response to infection Older age Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non- living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Proximal Subungual White Superficial Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Papillomatosis (Projections of dermal papillae) Secondary damage to nail matrix Loss of nail Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed Inflammation promotes ↑ fluid to tissues for ↑ immune cell delivery Widespread inflammation thickens parts of the epidermis in efforts to shed the infection Inflammation and epidermal hyperplasia (↑ growth of cells) influence local dermal papillae (group of cells just beneath the hair follicle) to proliferate and project above the skin Distal Subungual Superinfecting bacteria or other fungi proliferate beneath the compromised nail imparting a yellowish appearance Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Dermatophytes invade the proximal end of the nail plate Dermatophytes penetrate through the cuticle to the newly forming nail plate moving distally Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) Fungi predominantly invade various areas of the superficial nail plate layers eventually joining together White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses) The entirety of the nail plate is infected by the dermatophytes Widespread inflammation thickens the nail plate as well as beneath the nail (subungual hyperkeratosis) in efforts to shed the infection Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Local spread of infection Dermatophytes spread causing cracks in the skin deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Fissure (splits in the skin) Bacteria enters lymphatics and bloodstream Cellulitis Sepsis Onycholysis (nail plate separates from nail bed) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 13, 2024 on www.thecalgaryguide.com Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- compromised ↓ Immune response to infection Older age Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Proximal Subungual White Superficial Distal Subungual Superinfecting bacteria or other fungi proliferate beneath the compromised nail imparting a yellowish appearance Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed Inflammation promotes ↑ fluid to tissues for ↑ immune cell delivery Widespread inflammation thickens parts of the epidermis in efforts to shed the infection Inflammation and epidermal hyperplasia (↑ growth of cells) influence local dermal papillae (group of cells just beneath the hair follicle) to proliferate and project above the skin General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Papillomatosis (Projections of dermal papillae) Secondary damage to nail matrix Loss of nail Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Dermatophytes invade the proximal end of the nail plate Dermatophytes penetrate through the cuticle to the newly forming nail plate moving distally Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) Fungi predominantly invade various areas of the superficial nail plate layers eventually joining together White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses) The entirety of the nail plate is infected by the dermatophytes Widespread inflammation thickens the nail plate as well as beneath the nail (subungual hyperkeratosis) in efforts to shed the infection Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Dermatophytes spread deeper into toe Bacteria enters lymphatics and bloodstream Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Local spread of infection causing cracks in the skin Fissure (splits in the skin) Cellulitis Sepsis Onycholysis (nail plate separates from nail bed) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- Older compromised age ↓ Immune response to infection Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Papillomatosis (Projections of dermal papillae) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Secondary damage to nail matrix Loss of nail Proximal Subungual White Superficial Distal Subungual Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses) Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Local spread of infection causing cracks in the skin Dermatophytes spread deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Onycholysis (nail plate separates from nail bed) Fissure (splits in the skin) Bacteria enters lymphatics and bloodstream Cellulitis Sepsis Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Dermatophyte Onychomycosis: Pathogenesis and clinical findings Authors: Holly Zahary Loreman Reviewers: Mina Youakim Elise Hansen Shahab Marzoughi Jodi Hardin* * MD at time of publication Host Risk Factors Environmental Risk Factors Immuno- Older compromised age ↓ Immune response to infection Peripheral vascular disease Reduced blood circulation Diabetes Pre-existing nail dystrophy Previous nail trauma Integrity of nail unit is compromised Micro- traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit High blood sugar favoring infection Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Tinea infection (e.g. Tinea Pedis, Corporis, Capitis) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis Dermatophytic infection of the nail bed Proximal Subungual White Superficial General Symptoms (All Subtypes) Spongiosis (Intercellular edema) Acanthosis (Thickening of stratum spinosum layer of epidermis) Papillomatosis (Projections of dermal papillae) Hyperkeratosis (Thickening of stratum corneum In effort to rid infection) Secondary damage to nail matrix Loss of nail Distal Subungual Distal Subungual Subtype (Thick yellow nails, keratin and debris accumulate distally underneath nail plate) Proximal Subungual Subtype (Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression) White Superficial Subtype (Chalky white scale that spreads slowly beneath nail plate, well- defined “white islands” that coalesce as disease progresses) Total Dystrophic Subtype (End-stage nail disease, entire nail becomes thick and dystrophic) Local spread of infection causing cracks in the skin Dermatophytes spread deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Onycholysis (nail plate separates from nail bed) Bacteria enters lymphatics and bloodstream Fissure (splits in the skin) Cellulitis Sepsis Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Dermatophyte Onychomycosis (Tinea Unguium): Pathogenesis, clinical findings, Authors: Holly Zahary Loreman Reviewers: Elise Hansen Name Name* * MD at time of publication and complications Host Risk Factors Environmental Risk Factors Immuno- compromised ↓ immune response to infection Older age Peripheral vascular disease Diabetes Pre-existing nail dystrophy Previous Nail Trauma Integrity of nail unit is compromised Micro-traumatic pressure on nail Dark, warm shoe environment Optimal conditions for fugal growth Exposure to tinea pedis or onychomycosis Direct spread of infection to nail unit Reduced blood circulation High blood sugar, favoring infection Tinea pedis infection (see ‘Tinea Capitis, Tinea Corporis, and Tinea Pedis’) Infection spreads to distal hyponychial space Dermatophytes colonize local tissue in nail plate and nail bed Dermatophytes feed on keratinized tissue Proximal Subungual White Superficial Dermatophytes invade corneocytes on stratum corneum, the uppermost non-living layer of keratinized skin Compromise/breaking of hyponychial seal or cuticle (connection between hyponychium and nail plate) Keratinocytes produce an acute, low-grade inflammatory cytokine response Onychomycosis (Tinea Unguium) (dermatophytic infection of the nail bed) Distal Subungual General Symptoms (All Subtypes) Spongiosis Intercellular edema Acanthosis Thickening of stratum spinosum layer of epidermis Papillomatosis Projections of dermal papillae Hyperkeratosis Thickening of stratum corneum In effort to rid infection Secondary damage to nail matrix Loss of nail Distal Subungual Subtype Thick yellow nails, keratin and debris accumulate distally underneath nail plate Proximal Subungual Subtype Whitish discolouration of nail plate that begins proximally and moves distally, indicative of immunosuppression White Superficial Subtype Chalky white scale that spreads slowly beneath nail plate, well-defined “white islands” that coalesce as disease progresses Total Dystrophic Subtype End-stage nail disease, entire nail becomes thick and dystrophic Local spread of infection causing cracks in the skin Dermatophytes spread deeper into toe Abnormal keratinization in hyponychium Keratin accumulates between nail plate and hyponychium Onycholysis (nail plate separates from nail bed) Tissue Damage Cellulitis Sepsis Bacteria enters lymphatics and bloodstream Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com

Neonatal Necrotising Enterocolitis in Premature Neonates

Neonatal Necrotising Enterocolitis (NEC) in Premature Neonates: Pathogenesis and clinical findings Prematurity risk factors ↓ Intestinal motility ↑ Intestinal stasis allows bacteria more time to proliferate Bacterial overgrowth in gut ↓ Goblet cells in intestinal epithelium ↓ Intestinal mucus layer production leads to impaired mechanical defense against pathogenic bacteria Immature tight junctions in intestinal epithelium ↑ Permeability of intestinal epithelial barrier ↑ Toll-like receptor 4 (TLR4) expression on intestinal epithelial cells Aberrant bacterial colonization of gut Impaired gut barrier allows for ↑ bacterial translocation across intestinal epithelium TLR4 on intestinal mesentery endothelial cells bind lipopolysaccharides (LPS) on Gram-negative gut bacteria Immune cells release proinflammatory mediators (TNF, IL-12, IL-18) Cytokines mediate ↑ enterocyte apoptosis (including enteric stem cells) and ↓ enterocyte proliferation Intestinal mucosa healing is impaired, leading to local inflammation & injury TLR4 on intestinal epithelial cells binds LPS from Gram-negative gut bacteria Authors: Rachel Bethune Naima Riaz Reviewers: Nicola Adderley Michelle J. Chen Kamran Yusuf* Jean Mah* * MD at time of publication Endothelial nitric oxide synthase expression is reduced Vasoconstriction from ↓ NO reduces blood flow to intestines Prolonged ↓ in O2 perfusion results in irreversible intestinal mucosal cell death (necrosis) Gas escapes into abdominal cavity Leakage of intestinal contents irritates parietal peritoneum Bacteria enter bloodstream Pneumo- peritoneum Abdominal distention Peritonitis Sepsis Blood from tissue damage mixes with intestinal contents Bloody stool Intestinal sensory neurons detect damage and send signals to medullary vomiting centre Bilious vomiting Damaged intestinal cells are unable to absorb nutrients Short gut syndrome Persistent intestinal mucosal injury creates penetrating lesions through intestinal wall Intestinal perforation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 6, 2019; updated Mar 21, 2024 on www.thecalgaryguide.com

Lichen Sclerosus

Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen under the epidermis Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the overall skin thickness Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Normal Skin Lichen Sclerosus Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Hypopigmented patches (localized, pale areas of skin) Epidermal atrophy (crinkling paper-type skin appearance) Thinned skin is weakened and prone to physical stress or trauma ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Fibrotic tissue deposition following healing of damaged tissue Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Scarring Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 25, 2024 on www.thecalgaryguide.com Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen under the epidermis Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Thinned skin is weakened and prone to physical stress or trauma Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Normal Skin Lichen Sclerosus Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Fibrotic tissue deposition following healing of damaged tissue Scarring Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Chronic inflammation (i.e. chronic Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Thinned skin is weakened and prone to physical stress or trauma Lichen Sclerosus Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Normal Skin Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Fibrotic tissue deposition following healing of damaged tissue Scarring Chronic inflammation (i.e. chronic Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation of CD4+ and CD8+ T cells released from macrophages in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro- inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Normal Skin Lichen Sclerosus Skin fissures (linear cleavage of skin) Erosion/ulceration Fibrotic tissue deposition following healing of damaged tissue Scarring Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction T-cells proliferate in a band (horizontal linear) formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Localized histamine release Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Skin fissures (linear cleavage of skin) Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Scarring Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Erosion/ulceration Fibrotic tissue deposition following healing of damaged tissue Normal Skin Lichen Sclerosus Chronic inflammation (i.e. chronic Elise Hansen Unknown triggers Genetic predisposition infection, chronic toxin exposure) Medications (e.g. carbamazepine, (HLA-DQ7 and HLA-DR12) and trauma pembrolizumab, nivolumab, ipilimumab) ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction Sunawer Aujla Shahab Marzoughi Name Name* * MD at time of publication T-cells proliferate in a band (horizontal linear) formation Pro-inflammatory response activation (increase in pro-inflammatory cytokines such as Interleukins 1-alpha and 1-beta) ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Hypopigmented patches (localized, pale areas of skin) Histamine receptor binding stimulates sensory nerve endings Localized area appears red Localized histamine release Localized vasodilation (↑ blood flow) Superficial dermal edema (swelling) Pruritus Erythema Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Normal Skin Sclerotic plaques (localized areas of thickened skin) Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Skin fissures (linear cleavage of skin) Bleeding Erosion/Ulceration Epidermal atrophy (crinkling paper- type skin appearance) Lichen Sclerosus Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Fibrotic tissue deposition following healing of damaged tissue Scarring Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Name Name* * MD at time of publication Pruritus Histamine receptor binding stimulates sensory nerve endings Localized area appears red Erythema Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction T-cells proliferate in a band formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) Localized histamine release Localized vasodilation (↑ blood flow) Superficial dermal edema (swelling) Collagen deposits and hyalinizes beneath the atrophic epidermal layer Hypopigmented patches (localized, pale areas of skin) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Skin fissures Lichen Sclerosus Epidermal atrophy (crinkling paper- type skin appearance) Sclerotic plaques (localized areas of thickened skin) Bleeding Scarring Erosion/Ulceration Normal Skin Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Post-Renal Acute Kidney Injury AKI

Post-Renal Acute Kidney Injury (AKI): Pathogenesis and clinical findings Blood clot or cellular debris Foreign body Neurogenic bladder Obstruction intrinsic to urine excretion system Nephrolithiasis (kidney stones) Anatomical defect(s) Intra- abdominal adhesions Retroperitoneal fibrosis (scar-like tissue) Benign or malignant masses Prostate cancer Benign prostatic hyperplasia ↓ Urine flow across point of obstruction Obstruction extrinsic to urine excretion system Urine buildup distends urine collecting system (hydronephrosis) Compression of renal vasculature due to mass effect ↑ Volume/pressure proximal to obstruction ↑ Intratubular pressure ↓ Pressure gradient between glomerular afferent arteriole and Bowman’s space Casts occlude tubules ↓ Filtration of plasma into nephrons ↓ Glomerular Filtration Rate (GFR) Obstruction is relieved ↓ Intratubular pressure Rapid GFR ↑ Rapid diuresis of fluid and electrolytes Dilated pelvicalyceal system on ultrasound ↓ Urine output ↓ Venous drainage and arterial supply Local ischemia and inflammation of kidney Impaired resorption, excretion, and fine tuning by tubules Acute Tubular Necrosis (ATN) with granular casts ↓ Urine output ↓ Clearance of free water and solutes ↑ Intravascular volume ↑ Serum creatinine ↓ Medullary solute concentration, ischemia, ↓ response of collecting ducts to antidiuretic hormone Lasts > 24hrs Post-obstructive diuresis causes hypovolemia and electrolyte derangements Authors: David Campbell, Matthew Hobart Reviewers: Raafi Ali, Luiza Radu Huneza Nadeem, Marissa Zhang, Julian Midgley* * MD at time of publication Resolves < 24hrs in euvolemia Physiologic post- obstructive diuresis ↑ Na+ and Cl- delivery to distal convoluted tubule is sensed by macula densa Secretion of adenosine by macula densa Adenosine constricts afferent arterioles ↓ GFR ↓ Renal clearance of drugs and waste products ↑ Venous hydrostatic pressure ↑ Volume in arterial system overwhelms pressure regulation mechanisms Hypertension Fluid extravasation from veins and capillaries Generalized Edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 25, 2024 on www.thecalgaryguide.com

Irritant Contact Dermatitis Pathogenesis and Clinical Findings

Irritant Contact Dermatitis: Pathogenesis and clinical findings Authors: Zaini Sarwar, Mina Youakim Reviewers: Shahab Marzoughi, Ryan T. Lewinson, Yan Yu*, Laurie M. Parsons* * MD at time of publication Repeated/chronic exposure causes damage to cell membranes Skin barrier disruption Chronic non-specific inflammatory response Repetitive keratinocyte cytokine-mediated injury Keratinocytes exhibit ↑ proliferation as a compensatory response Rapid turnover of stratum corneum (outermost layer of the epidermis) Hyperkeratotic skin is less amenable to skin stretching and pressure Skin fissures (cracks in the skin) Irritant agents (abrasives, cleaning solution, oxidative & reducing agents, dust, soils, water) Acute exposure triggers inflammatory response Keratinocytes undergo cytotoxic damage with ↑ neutrophil & cytokine release Common occupational exposures (housekeeping, cleaning, catering, medical/dental, construction) Risk factors (atopy, fair skin, low temperature, low humidity) Stimulation of local nociceptors (free nerve endings extend into the mid epidermis) Perivascular (around the blood vessel) inflammation causes histamine release from mast cells Damaged keratinocytes are destroyed via apoptosis (programmed cell death) Epidermal Necrosis (death of epidermal tissue) Shedding of necrotic tissue Ulceration (deep open wound on skin) Burning pain (uncomfortable stinging sensation) Pruritus (itching) Histamine causes local blood vessel dilation and ↑ blood flow to the area of skin affected Erythema (area appears red from ↑ blood flow) Burning & Itching Spongiosis Neutrophils Neutrophils Histamine causes local blood vessel walls to have ↑ permeability, thereby ↑ leakage of fluid Spongiosis (↑ fluid between keratinocytes in the epidermis) Fluid continues to build up from ongoing inflammation Vesiculation (fluid collections in the epidermis) Long-term skin scratching causes chronic irritation which eventually hardens the skin Lichenification (thick, hardened patches of skin) ↑ Overall keratin production Hyperkeratosis (thickening of the outermost skin layer) Further fluid buildup bursts vesicles leaving behind erosions and dried crust on the epidermis Crust (scaling over the skin) Lichenification Erosions (open sore on skin) Ulcer Epidermis Perivascular Inflammation Hyperkeratosis Dermis Dermal-epidermal junction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 19, 2016; updated Mar 30, 2024 on www.thecalgaryguide.com

Deep Partial Thickness Burns Pathogenesis and Clinical Findings

Deep Partial Thickness Burns: Pathogenesis and clinical findings Radiation (Sunlight, x-ray, nuclear emission/explosion) Ionizing radiation gets into contact with DNA Damage to keratinocytes Fire (Flash fire or direct contact with flame) Contact (Hot solid objects) Scalding (Hot liquid via immersion, spill or splash) Chemical (Strong acid, alkali or irritant gas) Electrical (Contact with exposed electrical wiring/appliances) Author and Illustrator: Amanda Eslinger Maharshi Gandhi Reviewers: Alexander Arnold Shahab Marzoughi Duncan Nickerson* * MD at time of publication Direct transfer of heat energy Coagulation necrosis (cell death due to ischemia) is induced Deep Partial Thickness Burn Injury to the epidermal layer and both the papillary and a portion of the reticular layer of the dermis Transfer of heat energy & direct injury to cellular membranes Epidermis Papillary dermis Reticular dermis Sub- cutaneous Tissue ↑ vascular permeability due to damage Fluid leak results in edema between dermal & epidermal layer Blisters (a bubble on the skin containing fluid) Thin epidermal layer forming fluid-filled vesicle breaks open Cutaneous capillary bed is destroyed Blood flow to injured area is compromised Pressing on the skin doesn’t easily force blood cells out of the area Non-blanchable skin Vasodilation in fascia (a thin casing of connective tissue) underlying subcutaneous tissue Inflammatory mediators such as cytokines and prostaglandins activate fibroblasts Collagen deposition and subsequently induration (thickening of skin) Some healthy dermal appendages surrounded by islands of undamaged epithelial cells Possible spontaneous re-epithelialization in 2-9 weeks During re-epithelization of burns there can be excessive deposition of collagen and other extracellular matrix components Thick raised scars in dermis due to excess collagen deposition Somatosensory structures (nociceptors, thermoreceptors, and mechanoreceptors) are completely injured within the dermis Analgesia of impacted area (the inability to feel pain) Ongoing Inflammation and dilated blood vessels Red Induration (Thickened skin appearing red) Compromised blood flow and more extensive tissue damage White Induration (Thickened skin appearing white) Moist Wound Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 2, 2013, updated Apr 20, 2024 on www.thecalgaryguide.com

Costochondritis

Costochondritis: Pathogenesis and clinical findings Systemic infection originating in upper respiratory tract (commonly Staphylococcus aureus and Streptococcus bacterial infections) Infection spreads through blood to ribcage and chest wall Age-related degeneration of cartilage within ribcage joints Immune cells present in joints secrete proinflammatory cytokines Cytokines sensitize nociceptors (pain receptors) in joints Repetitive trauma or strain to chest wall muscles (e.g. chronic cough, chest wall injury, overexertion of chest wall muscles) Excessive stretch and tearing of ribcage cartilage and ligaments Autoimmune disease (e.g. rheumatoid arthritis) Antigen presenting cells display self-antigens to CD4+ T cells Mechanical stimuli (e.g. Damaged cells release cytokines Pathogens activate immune cells at site of stretch) activate nociceptors that recruit immune cells inflammation Costochondritis Benign inflammation of the ribcage (costal) cartilage, particularly at the costosternal junctions (connection between sternum and cartilage) and the costochondral junctions (connection between the cartilage and rib) Authors: Michelle J. Chen Reviewers: Raafi Ali Yan Yu* Gerhard Kiefer* * MD at time of publication Cartilage, ligament, or muscle injury Presence of foreign pathogen in costal cartilage Injury or pathogen activates inflammatory cascade in the ribcage cartilage Immune cells proliferate so that they exceed the available space in the cartilage matrix of the ribcage Cartilage swelling compresses intercostal nerves Compression acts as a mechanical stimulus to activate nociceptors Sharp, localized pain reproducible upon palpation over ribcage Immune cells secrete cytokines Cytokines activate nociceptors so that they become more sensitive to mechanical stimuli Muscle or ligament stretch from normal use activates sensitized nociceptors Pain increases with inspiration or cough Natural resolution of inflammation over time Macrophages phagocytose apoptotic cells (immune and cartilage cells) and cellular debris Immune cells release factors that degrade proinflammatory cytokines Fewer cytokines reduce immune cell recruitment into costal cartilage Pain usually self-resolves Immune cells release lipid molecules that bind to the same cells (autocrine signaling) to inhibit further production of inflammatory cytokines and chemokines Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 29, 2024 on www.thecalgaryguide.com

Acute Otitis Media Complications

Acute Otitis Media: Complications Prolonged mucus buildup or swelling in Eustachian tube due to colds/allergies obstructs the Eustachian tube Fluid unable to drain through tube and accumulates in middle ear Acute Otitis Media Infection and inflammation of the middle ear Mastoid air cells are in physical contact with distal middle ear Pathogens move into mastoid air spaces Inflammation & infection in air spaces Mastoiditis Bacterial and immune cell debris (pus) accumulates in mastoid air spaces Untreated middle ear infection allows further bacterial proliferation Persistent effusion causes ion channel changes in inner ear Composition of endolymph and perilymph in inner ear changes Vestibular/Labyrinth dysfunction Feelings of Vertigo imbalance Purulent discharge from middle ear through perforation Otorrhea (ear discharge) ↑ Pressure in middle ear Pressure stretches tympanic membrane Cytokines reach hypothalamus through the bloodstream Hypothalamus responds to stimulation and ↑ thermoregulatory set-point High-grade fever Infection spreads into bloodstream Sepsis Cytokines alter metabolism pathways of neurotransmitters in the brain Cerebral cortex dysfunction Infection spreads to cranium Intracranial complications (e.g., meningitis, brain abscess, thrombus) Author: Jody Platt Stephanie de Waal Reviewers: Yan Yu Elizabeth De Klerk William Kim Annie Pham Michelle J. Chen Danielle Nelson* * MD at time of publication Helper T cells and macrophages release inflammatory cytokines into the bloodstream Perforation of tympanic membrane ↓ Conduction of sound waves Conductive hearing loss Pressure in middle ear diffuses out of perforation ↓ Tympanic membrane stretching Otalgia (ear pain) fades Accumulated debris compresses cranial nerve VII Facial nerve palsy Mastoid abscess Febrile seizures Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 28, 2013, updated Apr 29, 2024 on www.thecalgaryguide.com

Sickle Cell Disease Pathogenesis Clinical Findings and Complications

Sickle Cell Disease: Pathogenesis, Clinical Findings, and Complications DNA point mutation in chromosome 11 causes a substitution of glutamate to valine for the sixth amino acid of the β-globin chain Authors: Yang (Steven) Liu Priyanka Grewal Reviewers: Alexander Arnold Luiza Radu JoyAnne Krupa Yan Yu* Lynn Savoie* * MD at time of publication Hemoglobin S (HbS) variant formed instead of normal Hemoglobin A (HbA) Hb electrophoresis shows approximately 45% HbS, 52% HbA (ααββ), 2% HbA Hb electrophoresis shows approximately 90% HbS, 8% HbF, & 2% HbA . No HbA present (ααδδ), & 1% HbF (ααγγ;2 fetal hemoglobin) Heterozygous: point mutation in one of the two chromosomes (Hb AS) Sickle cell trait (asymptomatic unless severely hypoxic) Homozygous: point mutation in both chromosomes (Hb SS) Sickle cell disease An inherited blood disorder characterized by defective hemoglobin that leads to red blood cells sickling 2 Dehydration Hypoxemia Acidosis ↓ Volume of RBC cytoplasm ↓ O2 Saturation of Hb O morereadily 2 released from Hb in low pH environment ↑ Concentration of deoxygenated HbSinred blood cells (RBCs) Hydrophilic glutamate→ hydrophobic valine substitution makes HbS less soluble in the cytoplasm & more prone to polymerization & precipitation in its deoxygenated state ↑ Concentration of deoxygenated Hb in RBC leads to ↑ polymerization rate Polymerized & precipitated HbS forms long needle-like fibers RBC shape becomes sickled Sickle cells on peripheral blood smear Vaso-occlusion (sickled RBCs lodge in small vessels, blocking bloodflow to organs & tissues) Blockage of venous outflow Occlusion of vessels in lungs ↑ pulmonary blood pressure Fluid extravasates into interstitial tissue leading to pulmonary edema Acute chest syndrome (chest pain, hypoxemia (↓blood oxygen), etc.)** to the penis: to the spleen: Priapism (persistent, painful erection) Splenic Sequestration (blood pools in spleenà splenomegaly & hypotension) Extravascular hemolysis (macrophages in the spleen phagocytose sickled RBCs) Normocytic anemia ↑Marrow erythropoiesis (RBC production) to compensate for hemolysis Infarction of bone Pain crises If occurring in hands Dactylitis (inflammation of digits) Blockage of arteries ↓ oxygenation of organs & tissues Vaso-occlusion of the splenic artery Splenic infarction (↓ blood supply leads to tissue death) RBC inclusions (structures found in RBCs) not removed by spleen Howell-Jolly bodies (RBC DNA remnants) on blood smear Vaso-occlusion of other arteries (cranial, renal, etc) Stroke, renal failure ↑ RBC breakdown ↑ Unconjugated bilirubin released from RBC breakdown RBC precursors (reticulocytes) are released into the blood stream Reticulocytosis (increased number of immature red blood cells) on peripheral blood smear Patient’s RBC level becomes dependent on increased marrow activity Bone marrow infarction or viral infections (i.e. Parvovirus B19) suppresses bone marrow activity Aplastic crises (profound anemia) ** See corresponding Calgary Guide slide(s) ↑ Serum level of unconjugated bilirubin Some of the circulating unconjugated bilirubin deposits in the skin Jaundice (yellowing of skin) ↑ Conjugation of bilirubin in liver ↑Amounts of conjugated bilirubin released into bile Gallstone formation Cholelithiasis (presence of gallstones in the gallbladder) Spleen releases invasive encapsulated bacteria (eg. Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis) into circulation, which causes infections Meningitis Sepsis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 16, 2013, updated Apr 29, 2024 on www.thecalgaryguide.com

Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS): Pathogenesis and clinical findings X-linked recessive inheritance (mostly males impacted) Spontaneous DNA mutation Genetic mutations in Wiskott-Aldrich Syndrome Protein (WASP) impair actin cytoskeleton remodeling in hematopoietic cells (immature blood cells) Authors: Mina Mina Reviewers: Hana Osman Mao Ding Maharshi Gandhi Shahab Marzoughi Louis-Philippe Girard* * MD at time of publication Megakaryocytes (platelet precursor cells) depend on the cytoskeleton changing shape to form pseudopodia (arm-like projections) which bud off forming cellular fragments (platelets) Abnormal cytoskeleton reorganization leads to ineffective thrombocytopoiesis (production of platelets) Microthrombocytopenia (↓ platelet size and quantity) Issues with formation of a platelet plug due to abnormal platelets (dysfunction of primary hemostasis) Reduced ability for platelet adhesion, activation, and/or aggregation Natural killer cells depend on the cytoskeleton reorganization to form immunological synapses (communication) with body cells in order to have effective surveillance T cells depend on the cytoskeleton remodeling to form pseudopods which allow them to synapse with other cells when a pathogen is encountered Defective immune synapse formation ↓ Cancer immunosurveillance ↑ Risk of malignancy Helper T cells cannot activate B cells which generate antibodies (immunoglobulins) to destroy pathogens Regulatory T cells can not sufficiently downregulate effector cells which typically limit the immune response and prevent autoimmune conditions ↑ Risk of autoimmune diseases Recurrent opportunistic infections Immune dysregulation Impaired immune response ↓ Number and function of T cells Immune responses contribute to Type 2 immune responses Atopic dermatitis (AD; chronic inflammation that causes itchy skin) ↑ Immunoglobulin (Ig) A Epistaxis (nosebleed) Red blood cells leak from capillaries Menorrhagia (heavy menstrual bleeding) Petechiae (small, flat, red spots that appear on the skin) Inflammation in AD triggers release of interleukins (modulatory proteins during inflammatory and immune responses) leading to Immunoglobulin (Ig) class switching ↑ IgE levels Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 20, 2024 on www.thecalgaryguide.com

Scabies pathogenesis and clinical findings

Scabies: Pathogenesis and clinical findings Direct person-person transmission of Sarcoptes Scabiei var. hominis to new host Fertilized females secrete proteolytic enzymes that allow them to burrow through the stratum corneum (2 mm/day) Authors: Heena Singh Amanda Eslinger Nirav Saini Reviewers: Shahab Marzoughi Danny Guo Yan Yu Richard Haber* * MD at time of publication Mechanical irritation and immunological reaction Mast cell activation and histamine release Itch (> 10 Mites) Stratum corneum Stratum lucidum Stratum granulosum Stratum spinosum Stratum basale Females lay 2-3 ova/day which hatch in the stratum corneum in pockets after 3 days The larvae molt and mature for 2 weeks and mate within the pockets of the stratum corneum Following mating, female mites begin burrowing Cycle is propagated as new female mites create more burrows in stratum corneum Superficial, Linear, Tortuous (i.e., Twisted) +/- Scaly Burrows ↑ Exposure to mite antigens such as Sar s 14.3 and Sar s 14.2 Type 2 helper T-cells produce proteins IL-4, IL-5, IL-13 ↑ Serum Immunoglobulin G & E ↑ Eosinophil Count in Peripheral Blood Inappropriate T helper-type immune response in skin (mechanism unknown) Antigens forming from mite feces, ova, or decomposing bodies Type IV hypersensitivity reaction (delayed immune response 2-4 weeks following initial contact) Skin barrier dysfunction from inflammation and histamine release Pre-existing immunosuppression Chronic inflammatory response Allergic reaction to ↑ mite activity at night Uncontrollable Itch (Worse At Night) + Excoriations (Scratch Marks) Urticarial (Hive-Like) Crusted Papules Eczematous Plaques Skin breakdown Opening for bacteria (commonly S. aureus) 2° Bacterial infection Pustules Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 17, 2013; updated Jun 9, 2024 on www.thecalgaryguide.com

Posterior Cruciate Ligament PCL Injury Pathogenesis and Clinical Findings

Posterior Cruciate Ligament (PCL) Injury: Pathogenesis and clinical findings Authors: Luc Wittig Stephanie de Waal Michelle J. Chen Reviewers: Reza Ojaghi Usama Malik Sunawer Aujla Nojan Mannani Mankirat Bhogal Dr. R. Buckley* Dr. Gerhard Kiefer* * MD at time of publication Sport-related trauma Dashboard knee injury from a motor vehicle collision Tibia contacts dashboard at high velocity with knee in flexed position Tibia is forced posteriorly, relative to knee joint The PCL undergoes sudden & forceful strain Hyperextension injury (knee joint moves past its normal extension limit) Extreme tibia movement anteriorly past knee joint overstretches PCL Hard fall on flexed knee Posterior Cruciate Ligament Injury Strain & overstretching of the PCL, which connects the anterior distal femur to the posterior proximal tibia to prevent posterior translocation of the tibia relative to the femur, can result in a partial or complete tear. The tear can be isolated (rare) or be one of multiple ligaments that are torn (multi-ligamentous tear). Mild injurious force causes a partial tear Intact portion of PCL prevents extreme tibial translocation posterior to the femur. Torn portion still allows 1-5 mm of posterior tibial translocation (Grade 1) Positive posterior drawer test Knee injury tests • Posterior drawer test – Push against leg below the knee to test for posterior tibial translocation relative to femur • Lachman test – Pull leg below the knee to test for anterior tibial translocation relative to femur • McMurray test – Tests for medial and lateral meniscus tears • Varus & valgus stress test – Tests for medial and Strong injurious force causes a complete, isolated tear PCL is unable to prevent posterior translocation of the tibia relative to the femur, allowing 6-10 mm of posterior tibial translocation (Grade 2) Positive posterior Negative Lachman, McMurray, drawer test and varus & valgus stress test Very strong injurious force causes a multi- ligamentous tear and damage to the knee joint capsule (capsuloligamentous injury) Absence of stability from PCL combined with absence of stability from other knee ligaments allows for > 10 mm of posterior tibial translocation (Grade 3) Positive posterior Positive Lachman OR McMurray drawer test OR varus & valgus stress test PCL unable to stabilize knee by preventing posterior tibial translocation (chronic PCL insufficiency) Body uses quadriceps tendon for knee stabilization to compensate for PCL insufficiency Inflammation from injury contributes to progressive degenerative articular changes lateral collateral ligament tears Post-traumatic patellofemoral pain Osteoarthritis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 20, 2018; updated Jun 9, 2024 on www.thecalgaryguide.com

Migraines and auras pathogenesis and clinical findings

Migraines and Auras: Pathogenesis and clinical findings Genetic mutations at certain loci (e.g., Familial hemiplegic migraine mutation in gene encoding P/Q-type Ca2+ channels) Personal triggers (e.g., lack of food, emotional stress) “Cortical Spreading Depolarization” followed by “Cortical Spreading Depression” across one cortical hemisphere Cortical spreading depression creates “auras” via unknown mechanism(s) Expanding scotoma (area of visual blurriness) Spreading paraesthesias (numbness that travels across body) Dysphasic language (trouble finding words) Brainstem symptoms (e.g., vertigo, tinnitus) Motor symptoms (e.g., hemiplegia) Triggering of a depolarization wave in a unilateral region of the cortex with associated ↑ blood flow to that region Neurons and glia release K+ into extracellular space that spreads depolarization wave to nearby cortical areas Ion gradient imbalances cause Prolonged vasoconstriction neurons in original cortical area to and ↓ blood flow swell and become inhibited Activation of the hypothalamus (responsible for maintaining homeostasis) Prodromal symptoms (↑ thirst, hunger, yawning, ↓ cognitive function) Author: Yan Yu Braxton Phillips Reviewers: Shahab Marzoughi Owen Stechishin Dustin Anderson Scott Jarvis* Sina Marzoughi* * MD at time of publication Release of hypothalamic neurotransmitters (e.g., orexins, neuropeptide Y) at the trigeminalcervical complex (TCC) of the brainstem and cervical spinal cord Depolarizing wave passes over pseudounipolar neurons (neurons with two axons) of the trigeminal ganglion which synapse in brainstem & dura matter These neurotransmitters reduce the activation threshold of spinal trigeminal nucleus neurons in the TCC Neuropeptides (e.g., calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide) are released at the TTC, triggering local inflammation (termed neurogenic inflammation) Ongoing neurogenic inflammation activates secondary nociceptive neurons in the TTC Central sensitization (↓ response threshold of secondary nociceptive neurons in the TTC) Brain perceives referred pain from the face as the TTC also receives convergent nociceptive input from the face Facial allodynia (pain with normally non-painful stimuli) Serotonin & histamine are released on dural blood vessels triggering neurogenic inflammation in the dura matter Ongoing neurogenic inflammation activates primary nociceptive neurons in the dura matter Peripheral sensitization (↓ response threshold of primary nociceptive neurons around the dural blood vessels_ Unknown mechanisms no longer believed to be related to dural blood vessel dilation Unilateral throbbing headache Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 22, 2012, updated Jul 1, 2024 on www.thecalgaryguide.com

Legg Calve Perthes Disease

Legg-Calvé-Perthes Disease: Signs and Symptoms Idiopathic abnormalities in the common pathway of the blood clotting cascade ↑ blood thickness Initial stage (6 months) Early interruption of blood supply to femoral head ↓ Venous outflow from intraosseous vasculature ↑ pressure within bone Fragmentation stage (8 months) Body replaces resorbed necrotic bone with structurally weaker bone Backup of blood within bone vasculature impedes arterial inflow Temporary interruption of blood supply to proximal femoral epiphysis primarily during childhood Residual stage Differential growth of proximal femoral epiphysis Overgrowth of greater trochanter Healing stage (4 years) Body gradually replaces necrotic bone with stronger, more dense bone Lack of O2 & nutrients disrupts normal bone growth Bone tissue begins dying from loss of O2 & nutrients (osteonecrosis) Osteonecrosis is associated with inflammation of synovial tissue (synovitis) at the femoral head Metaphyseal cyst (area of bone resorption) grows on proximal femoral neck metaphysis Growth plate abnormalities Femoral bone head deformity Limited hip internal rotation & abduction Antalgic gait Femoral epiphysis collapses laterally and extrudes from acetabulum Femoral head now composed of dense and less dense bone Scattered radiolucency & radiodensity on plain radiographs Femoral head deformity becomes set in place and limits hip range of motion Femoral bone head deformity Limb length discrepancy Normal bone density on plain radiographs Abnormal articulo- trochanteric distance (vertical distance between highest point of greater trochanter & highest point of femoral head) Remodeling of femoral head & acetabulum seen on plain radiographs Growth plate irregularity ↓ Range of motion Widened medial joint space Antalgic gait Femoral head is displaced laterally Fragmented epiphysis on plain radiographs Groin pain & referred pain to anteromedial thigh or knee region Authors: Janelle Wai Michelle J. Chen Reviewers: Patrick Pankow Nojan Mannani Kirat Bhogal Dr. Gerhard Kiefer* * MD at time of publication Findings on magnetic resonance imaging (MRI) & plain radiographs Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 19, 2024 on www.thecalgaryguide.com

Acute Otitis Media Pathogenesis and Clinical Findings in Children

Acute Otitis Media in Children: Pathogenesis and clinical findings Congenital conditions (e.g. Down Syndrome, Pierre Robin syndrome) Exposure to tobacco smoke Impaired macrophage function in nasopharynx Lack of immunizations Lack of breastfeeding Infant does not receive antibodies from breast milk Overcrowding Age 6 – 16 months Immune system deficiencies Close proximity of kids & ↓ sanitation (e.g. daycare) ↑ Infection risk Upper Respiratory Tract Infection (i.e. bacterial (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis), viral) Immature Eustachian tube anatomy which facilitates pathogen transmission to middle ear Author: Jody Platt Stephanie de Waal Reviewers: Yan Yu Elizabeth De Klerk William Kim Annie Pham Michelle J. Chen Danielle Nelson* * MD at time of publication Abnormal anatomical structure (e.g. cleft palate) ↑ Nasopharyngeal streptococcus pneumoniae Lack of immunity to pathogens ↑ Colonization of nasopharynx with bacterial pathogens Inflammation & edema of respiratory mucosa including the nose, nasopharynx, and Eustachian tube Obstruction of the Eustachian tube Air from middle ear resorbs into circulation which creates a low-pressure environment Negative pressure gradient pulls viral/bacterial pathogens into middle ear Degenerating white blood cells, tissue debris, and microorganisms accumulate & develops into purulent effusion Inflammation & infection of middle ear Complications of acute otitis media** ↑ Pressure in middle ear Stretching of tympanic membrane Helper T cells & macrophages release cytokines into the bloodstream Cytokines trigger hypothalamus to ↑ thermoregulatory set-point Effusion behind tympanic membrane Effusion obstructs visualization of ossicles Neutrophils infiltrate middle ear & phagocytose pathogens Pus accumulates behind the tympanic membrane Blood vessels of the tympanic membrane vasodilate Bulging tympanic membrane Otalgia (ear pain) Discomfort disrupts daily activities in young children Fever Irritable Poor feeding Tympanic membrane erythema Painful blisters on tympanic membrane (e.g. Bullous myringitis) Can persist for up to 3 months after infection resolves Loss of tympanic membrane landmarks (i.e. handle of malleus, light reflex) ** See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 28, 2013; updated Aug 25, 2024 on www.thecalgaryguide.com

Low Ankle Sprain

Low Ankle Sprain: Pathomechanics and Clinical Findings Authors: Parker Lieb, Joseph Kendal Illustrator: Erica Lindquist Reviewers: Liam Thompson, Tara Shannon, Sunawer Aujla, Stephanie de Waal, Amanda Eslinger, Dave Nicholl, Maninder Longowal Gerhard Kiefer* *MD at time of publication Ankle eversion beyond normal range (less common) Excessive stress to medial ankle deltoid ligament Ankle plantar flexion and inversion beyond normal range (most common) Excessive stress to lateral ankle ligament(s) Associated fracture of malleolus or subtalar joint Bone pain, inability to weight bear Recruitment of inflammatory cells to damaged area ↑ Local pro- inflammatory cytokines ↑ Capillary permeability & vasodilation to damaged area Collagen fibers in ligament(s) rupture Low Ankle Sprain (medial or lateral) Local blood vessels tear Blood leaks into surrounding tissue Grade I Mild injury Grade II Moderate injury Grade III Severe injury Minimal ligament disruption Incomplete ligament tear Complete ligament tear No joint laxity Joint laxity Gross joint laxity Mechanical and functional instability Decreased ankle joint space Ankle Impingement (compression of soft and/or bony structures in joint) Chronic ankle instability Talus subluxation with anterior force on heel + Anterior drawer test Recurrent sprains Synovial inflammation & hypertrophy Remodeling of collagen and bone Degenerative changes (e.g., osteophytes, subchondral sclerosis) Damage to mechanoreceptors in muscles surrounding ankle joint Bruising Swelling Focal tenderness over torn ligament(s) Pain on injury and with weight bearing Impaired proprioception & neuromuscular control Nociceptors activated by trauma and inflammatory factors Falls Antalgic gait Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 9, 2014; updated Aug 15, 2023 on www.thecalgaryguide.com

Hypomagnesemia

Hypomagnesemia: Physiology Hyperglycemia An increased amount of glucose enters renal tubules as glomerulus performs blood filtration ↑ [Solute] in renal tubules from ↑ glucose content exerts osmotic force that pulls water & electrolytes, including Mg2+, into renal tubules ↑ Urinary Mg2+ excretion Lack of insulin Lack of insulin receptor signaling in distal convoluted tubule (DCT) ↓ glucose uptake from renal tubules Hypercalcemia Ca2+ binds to Ca2+ sensing receptors on thick ascending limb (TAL) of loop of Henle, where resorption of Ca2+ & Mg2+ occurs Receptor activation ↓ Na-K- 2Cl (NKCC) transporter activity which maintains electro- chemical gradient in TAL Passive paracellular resorption of Ca2+ and Mg2+, dependent on electrochemical gradient, ↓ ↑ Extra- cellular fluid ↓ Resorption of Na+ & H2O from renal tubules Genetic disorders (e.g. Bartter syndrome, familial hypomagnesemia) Medications (e.g. loop & thiazide diuretics, certain antibiotics, calcineurin inhibitors) Some metabolic byproducts of these drugs are nephrotoxic Inability to absorb free fatty acids (FFAs) Mg2+, which associates with FFAs, is not absorbed through the gut Steatorrhea (fat in the stool) Mal- absorption (often due to inflammation or infection) & diarrhea Acute pancreatitis ↓ Lipase secretion from pancreas ↑ levels of undigested fats in small intestine ↓ Passive Mg resorption from tubules Mg saponification in necrotic fat 2+ Varying mechanisms causing defective Mg2+ re-absorption (e.g. impacts to PCT, TAL, DCT disrupting transporters and ion shifting; ↓ gut resorption of Mg2+) Nutrients & 2+ electrolytes are lost in stool undergoes Renal loss of magnesium Gastrointestinal loss of magnesium Hypomagnesemia Serum [Mg2+] < 0.7 mmol/L Impairs production and release of parathyroid hormone responsible for ↑ blood Ca2+ Hypocalcemia Muscle cells are unable to activate Mg2+ dependent ATP hydrolysis Impairs muscle relaxation and reduces the ability to stop muscular contraction Lack of Ca2+ disrupts neurotransmitter release and neuronal signaling Impairs rapid depolarization and repolarization during muscle contraction Neuromuscular excitability (large, rapid change in membrane voltage due to small stimulus) Delirium Apathy QRS widening and peaking of T waves on ECG Torsade de Pointes Constant muscle contraction compresses blood vessels Reduced blood supply to hands, wrists, feet, and ankles Trousseau sign (carpopedal spasm with inflation of BP cuff) Authors: Caroline Kokorudz Reviewers: Shyla Bharadia Allesha Eman Michelle J. Chen Dr. Adam Bass* * MD at time of publication Chvostek sign (facial muscle twitch with cheek touch) Seizures Tetany Weakness Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Acute Diverticulitis

Acute Diverticulitis: Pathogenesis and clinical findings Low fiber diet Authors: Candace Chan Yan Yu Wayne Rosen* Reviewers: Laura Craig Noriyah AlAwadhi Danny Guo Erica Reed Maitreyi Raman* Claire Song Shahab Marzoughi * MD at time of publication ↓ Colonic motility ↑ Stool transit time Formation of small dry stool Stool build-up and ↑ strain with bowel movements ↑ Pressure in the colonic lumen Constipation (difficulty passing stool) Obstipation (inability to pass any feces) Inherent weakness in the muscle layers of the colonic wall associated with immature collagen fibers and diminished wall elasticity Mucosal and submucosal layers of the colon wall push through a weak spot of the circular muscle layer Formation of diverticulum (sac-like protrusion of the colonic wall) Continued stress on diverticula causes micro- perforations of the diverticulum Inflammation of diverticula Mesentery and pericolic fat (fat surrounding the colon) attempt to wall off inflammation or perforations Stool bacteria escapes the colon Formation of abscess (accumulation of pus in response to the bacteria ) Pro-inflammatory cytokine release from nearby adipose tissue Hypothalamic thermoregulatory center increases core temperature set point Fever Irritation of parietal peritoneum Inflamed vessels are more permeable and fluid leaks from colonic vessels into the abdominal cavity Chronic low-grade inflammation triggers activation of pro-fibrotic factors and fibroblasts Excess production of extracellular matrix proteins Stimulation of somatic nerves sends pain signals to the brain Lower left quadrant abdominal pain Peritoneal signs (abdominal guarding, rigidity, rebound tenderness) ↓ Total circulating blood volume ↑ heart rate ↓ Jugular venous pressure Orthostatic hypotension (low blood pressure when standing after sitting/lying down) Gastrointestinal strictures and/or colonic obstruction Accumulation of micro- perforations further weakens intestinal wall Complete bowel perforation (medical emergency) Development of an abnormal connection (fistula) through the bladder, vagina, skin, or gut Abscesses Accumulation of fibrotic tissue narrows the intestinal lumen Fibrosis of colon Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published Oct 4, 2024 on thecalgaryguide.com

Epilepsy in Older Adults

Epilepsy in Older Adults: Pathogenesis and clinical findings Cerebrovascular disease (1⁄3 of cases), primarily ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage Ischemic and hemorrhagic injuries cause inflammation and nerve cell degeneration Glial cells (astrocytes and oligodendrocytes) proliferate around the lesion area to repair the damaged tissue Glial scar formation impedes neuronal reconnection and growth Alzheimer’s or Vascular Dementia Central nervous system disease (e.g. traumatic brain injury, prior meningitis, mass) Medications associated with hyponatremia (e.g. diuretics, antidepressants, antipsychotics, etc.) Cerebral edema Increased intracranial pressure Compression on structures and blood vessels Sleep deprivation Tau or amyloid deposition (abnormal protein aggregates in brain) Small vessel disease Increased delta wave activity Heightened neural excitability Decreased seizure threshold Elevated stress hormones (e.g. cortisol) Increased neuronal excitability and decreased inhibition Areas of tissue death, white matter changes & cortical irritability Structural and electrical brain changes Epilepsy: Neurological disorder characterized by increased susceptibility to recurrent unprovoked seizures Excessive, hypersynchronous & oscillatory network function Imbalance between excitatory and inhibitory activity Resultant seizure activity Atypical Seizure pattern; e.g. seem confused, stare into space, wander, make unusual movements, inability to answer questions Often atypical location in brain (limbic or neocortical) Focal seizures are more common than generalized Postictal paresis can last for days & disorientation, hyperactivity, wandering and incontinence may persist for 1 week Neurotransmitter dysregulation, neural network disruption, genetic factors, psychosocial factors Psychiatric comorbidities Authors: Anna Crone Reviewers: Anika Zaman, Rachel Carson, Raafi Ali, Luiza Radu, Gary Michael K Klein* * MD at time of publication Widespread structural changes and hippocampal atrophy Dementia Sub-optimal treatment results in ongoing and more frequent epileptic seizures Status epilepticus (higher mortality among older adults) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Cholesteatoma of middle ear

Cholesteatoma (of middle ear): Pathogenesis and clinical findings Authors: Emma Holmes Angela Mak Reviewers: Stephanie Cote Vaneeza Moosa Shahab Marzoughi William Kim Sunawer Aujla Kristine Anne Smith* * MD at time of publication Tympanic membrane perforation (e.g., acute otitis media, trauma) Squamous epithelium invasion & migration into middle ear Eustachian tube dysfunction (e.g., craniofacial abnormalities) Negative pressure Invagination of tympanic membrane Retraction pocket with keratin trapping & ingrowth Inflammation (e.g., upper respiratory tract infection, rhinitis) Mucosal lining of middle ear become hyperproliferative Squamous metaplasia Basal cell hyperplasia Invagination & epithelial ingrowth in basement membrane of the middle ear Theory of implantation due to trauma (e.g., during surgery) Implantation of skin into the middle ear through a defect in the eardrum Traps moisture Bacterial infection Erosion of external auditory canal Conductive hearing loss Labyrinthine fistula (abnormal communication between the inner ear and the surrounding structures) Leakage of perilymph Cholesteatoma Destructive growth of keratinizing squamous epithelium in the middle ear Bone erosion allows for secondary infection from outside the middle ear Chronic otitis media Migration of bacteria from middle to inner ear Intracranial infection (e.g., meningitis, parenchymal abscess) Acute otitis media Accumulation of keratinous debris Release of inflammatory molecules Release of osteoclasts Secretion of acid and proteinases Erosion of temporal bone Pressure change in the middle ear Aural polyp (growth in external or middle ear canal) Vertigo Coalescent mastoiditis (bone is remodeled and resorbed from pressure necrosis, inflammation, and increased osteoclastic activity) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome (CRPS): Pathogenesis and clinical findings Type 1 origin: CRPS arises spontaneously or from trauma without confirmed damage to nerves (e.g. surgery, nerve compression, fracture, tissue trauma, ischemia, sprain) Type 2 origin: CRPS arises from trauma with confirmed evidence of nerve damage Intense psychological stress is associated with ↑ severity of CRPS Peripheral nerve endings release ↑ levels of neuropeptides (e.g. substance P, bradykinin, calcitonin gene-related peptide) Vasodilation & protein extravasation in tissues ↑ Perfusion to motor cortex ↓ Grey matter volume in cortical pain regions ↓ Cortical grey matter volume & ↓ perfusion of cortex in limbic & sensorimotor areas Dysregulation of sympathetic nerve fibres Autonomic dysfunction Central nerve fibres ↑ release of proinflammatory cytokines while ↓ release of anti- inflammatory cytokines Central sensitization (threshold at which a central nerve transmits a signal is lowered so that it more readily transmits signals) Mechanical hyperalgesia (hallmark of central sensitization) Authors: Jessica Hammal Calvin Howard Reviewers: Sina Marzoughi Michelle J. Chen Scott Jarvis* * MD at time of publication Nociceptors (nerve endings detecting pain) on skin become activated ↑ Cytokine & nerve growth factor release Primary afferent (sensory) neurons release ↑ levels of inflammatory neuropeptides Peripheral sensitization (threshold at which a nerve transmits a signal is lowered so that it more readily transmits signals) Widespread neurogenic inflammation (inflammation due to activation of peripheral nerve fibres) Sustained and dysregulated pro-inflammatory state Hyperalgesia (↑ sensitivity to feeling pain) Sweat gland related changes: Edema, sweating changes, asymmetric sweating Allodynia (pain from a stimulus that doesn’t normally cause pain) Trophic changes (wasting of skin, muscle, tissues; thinning of bones; thickening/thinning of nails) Motor dysfunction ↓ Range of motion Immobile due to severity of pain Impaired vasodilation & vasoconstriction Temperature asymmetry Altered skin color (red, blue, pale) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 28, 2024 on www.thecalgaryguide.com

Renal manifestations of SLE

Systemic Lupus Erythematosus (SLE): Renal Manifestations Authors: Madison Turk Reviewers: Modhawi Alqanaie Mao Ding Luiza Radu Glen Hazlewood* * MD at time of publication Genetic susceptibility and potential environmental triggers (smoking, silica, Epstein-Barr Virus, hormones, ect) ↓Clearance of dead cell debris in the body (exact mechanisms unknown; See slide on pathogenesis of SLE) Extracellular exposure of nuclear proteins (which bind DNA and regulate gene expression) Immune cells respond to nuclear proteins as if they are non-self, as they usually don’t ‘see’ them Systemic Lupus Erythematosus An autoimmune disease characterized by anti-nuclear-antibody production resulting in widespread inflammation and tissue damage in varying affected organs, including one, or a combination of, joints, skin, brain, lungs, kidneys, and blood vessels Production of auto-antibodies against self nuclear proteins IC deposition in renal vessels Activation of inflammatory cells against IC’s causing vascular injury/inflammation ↑Clot formation in vessels leading to ↓vessel lumen diameter and ↓blood flow ↑Reninàcleavage of angiotensinogen to angiotensin Ià cleavage by angiotensin converting enzyme into angiotensin II Vessel constriction to ↑blood pressure (to ↑ renal blood flow) IC deposition in tubule basement membrane of the kidney Formation of immune complexes (IC) (collections of antigen(s), antibodies, and/or complement proteins bound together) Tubulointerstitial nephritis: (Inflammation of the renal tubules and interstitium, sparing the glomeruli) Renal ischemia IC deposition in the glomerulus Activation of complement, initiating an inflammatory response Recruitment of myeloid cells (monocytes/ neutrophils) Production of reactive oxygen species, cytokines and release of cytotoxic granules Tubular inflammation and damage resulting in ↓sodium reabsorption Renal release of reninà ↑ angiotensin I/II and resulting ↑ aldosterone ↑Sodium reabsorption, and potassium excretion in the collecting duct ↓Potassium secretion from the Distal Convoluted Tubule Hyperkalemia Hypokalemia ⍺-intercalated cell damage ↓Acid excretion Metabolic acidosis End stage kidney disease (all manifestations can result in this) Hypertension Tissue damage from the inflammatory response Glomerular nephritis (inflammation/damage of the filtering part of the kidneys) Fibrosis (thickening or scarring of tissue) Mesangial and parietal cell proliferation Podocyte injury ↑blood and protein excretion due to damage to the glomerular filtration membrane ↓protein in blood Edema Proteinuria Hematuria ↓Functional renal tissue to filter creatinine from blood ↓ Glomerular filtration rate ↑ Plasma creatinine Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 11, 2024 on www.thecalgaryguide.com

Diabetic Polyneuropathy

Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Raafi Ali Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia (↓ Intracellular insulin levels) ↓ Insulin induces expression of neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factor (IGF), & vascular endothelial growth factor (VEGF)) ↓ Stimulus for peripheral nerve maintenance & repair Impaired peripheral nerve repair Hyperglycemia (↑ Intracellular glucose levels) ↑ Glycolysis (breakdown of glucose) ↑ Intermediates & products of glycolysis (i.e. Protein Kinase C, AGE, polyols (sorbitol & fructose), NADH) Protein Kinase C Pathway activated & ↑ inflammation in endothelium, vascular smooth muscle, fibroblasts of blood vessels Prothrombotic state with ↑ vascular fibrosis, ↑ smooth muscle proliferation, ↑ chance of blood clots, ↑ impaired endothelial- mediated vasodilation Arterial stiffening & ischemia Advanced Glycation End Products (AGEs): end products of glycolysis that have carbohydrates attached AGEs bind AGE receptors on endothelium & white blood cells ↑ Inflammation, vascular permeability, procoagulant activity & monocyte influx Immune cells generate toxic reactive oxygen species as part of their defense system Polyol pathway activated in kidney, retina, nerves Excess glucose converted to sorbitol & fructose Metabolism of sorbitol & fructose produces intermediates that undergo auto-oxidation ↑ Reactive oxygen species ↑ NADH (reducing agent) overloads the electron transport chain ↑ Leakage of electrons in the electron transport chain ↑ Free radical formation (type of reactive oxygen species that is toxic to cells & tissues when in excess) ↑ Oxidative stress Diabetic Polyneuropathy (damage to & loss of peripheral nerve function due to nerve hypoxia & impaired repair mechanisms) Sensory axonal loss Damage to small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesia (pins & needles feeling), dysthesia (burning, tingling, itching) X-ray: destruction of weight-bearing foot joints Damage to large myelinated fibers Loss of vibratory sensation in glove & stocking pattern distribution; altered proprioception Claw toe deformity Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Distal motor axonal loss ↓ Ability of axons to transmit signals to central nervous system to foot muscles ↓ Foot muscle strength, ↓ Coordination & imbalance between toe extensors & flexors Weight shift creates pressure points Fissures in skin of weight-bearing areas Infection & chronic ulceration Damage to nerves that control contractions of stomach muscles Gastroparesis: stomach muscles weakened, ↓ motility & delayed transit of contents Autonomic neuropathy Damage to nerves that control heart blood flow, contractions & contractility Damage to nerves that control blood flow and arousal responses for sexual function Erectile dysfunction Orthostatic or postural hypotension Exercise intolerance Resting tachycardia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 28, 2014; updated Nov 16, 2024 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Raafi Ali Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia (↓ Intracellular insulin levels) ↓ Insulin induces expression of neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factor (IGF), & vascular endothelial growth factor (VEGF)) ↓ Stimulus for peripheral nerve maintenance & repair Impaired peripheral nerve repair Hyperglycemia (↑ Intracellular glucose levels) Protein Kinase C Pathway in endothelium, vascular smooth muscle, fibroblasts of blood vessels ↑ Inflammation Prothrombotic state with ↑ chance of blood clots, ↑ vasoconstriction & ↑ arterial stiffening Ischemia ↑ Glycolysis (breakdown of glucose) Advanced Glycation End Products (AGEs): end products of glycolysis that have carbohydrates attached AGEs bind cellular receptors Inflammation, vascular permeability, procoagulant activity & monocyte influx Immune cells generate toxic reactive oxygen species as part of their defense system ↑ Intermediates & products of glycolysis (i.e. Protein Kinase C, AGE, sorbitol & fructose, NADH) Polyol Pathway in kidney, retina, nerves Excess glucose converted to sorbitol & fructose Metabolism of sorbitol & fructose produces intermediates that undergo auto-oxidation ↑ Reactive oxygen species ↑ Leakage of electrons when NADH (reducing agent) overloads the electron transport chain ↑ Free radical formation (type of reactive oxygen species that is toxic to cells & tissues when in excess) ↑ Oxidative stress Diabetic Polyneuropathy (damage to & loss of peripheral nerve function due to nerve hypoxia & impaired repair mechanisms) Sensory axonal loss Damage to small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesia (pins & needles feeling), dysthesia (burning, tingling, itching) X-ray: destruction of weight-bearing foot joints Damage to large myelinated fibers Loss of vibratory sensation in glove & stocking pattern distribution; altered proprioception Claw toe deformity Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Distal motor axonal loss ↓ Ability of axons to transmit signals to central nervous system to foot muscles ↓ Foot muscle strength, ↓ Coordination & imbalance between toe extensors & flexors Weight shift creates pressure points Fissures in skin of weight-bearing areas Infection & chronic ulceration Damage to nerves that control contractions of stomach muscles Gastroparesis: stomach muscles weakened, ↓ motility & delayed transit of contents Autonomic neuropathy Damage to nerves that control heart blood flow, contractions & contractility Damage to nerves that control blood flow and arousal responses for sexual function Erectile dysfunction Orthostatic or postural hypotension Exercise intolerance Resting tachycardia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia ↓ intracellular insulin levels ↓ Neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, IGF, & VEGF) ↓ stimulus for peripheral nerve maintenance and repair Impaired peripheral nerve repair Sensory axonal loss Small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesias or tingling and numbness, dysthesias where sense of touch is distorted Hyperglycemia ↑ Intracellular glucose levels This produces an excess of glycolysis intermediates & products of glycolysis (i.e. sorbitol & fructose; AGE; Protein Kinase C) PKC Pathway in endothelium, vascular smooth muscle, fibroblasts of blood vessels ↑ inflammation Prothrombotic state with ↑ chance of blood clots; vasoconstriction & arterial stiffening Ischemia Advanced Glycation End Products: The body “glycates” end products of glycolysis, which means that some end products have a carbohydrate added to them Polyol Pathway in kidney, retina, nerves Excess glucose is converted to sorbitol and fructose, which accumulates in cells ↑ Oxidative stress ↑ Free Radical Formation AGE’s bind cellular receptors inducing inflammation, vascular permeability, procoagulant activity & monocyte influx Abbreviations: AGE – Advanced Glycation End Products IGF - Insulin-like Growth Factor VEGF - Vascular Endothelial Growth Factor PKC – Protein Kinase C Autonomic neuropathy Nerve hypoxia & impaired repair mechanisms leading to dysfunction & loss of peripheral nerves Distal motor axonal loss Large myelinated fibers Atrophy of intrinsic foot muscles Fissures in skin of weight-bearing areas Imbalance between toe extensors & flexors Weight shift results in pressure points Infection & chronic ulceration Gastroparesis: stomach muscles weakened with ↓ motility Claw toe deformity Erectile dysfunction Altered proprioception X-ray: destruction of weight-bearing foot joints Loss of vibratory sensation in glove & stocking pattern distribution Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Cardiac: Resting tachycardia, exercise intolerance, orthostatic or postural hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Amanda Eslinger Reviewers: Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia ↓ Neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, IGF, & VEGF) ↓ stimulus for peripheral nerve maintenance and repair Impaired peripheral nerve repair Sensory axonal loss Small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesias, dysthesias Hyperglycemia ↑ Intracellular glucose levels This produces of glycolysis an excess of glycolysis intermediates & products (i.e. sorbitol & fructose; AGE; Protein Kinase C) PKC Pathway PKC pathway activation results in ↑ inflammation Prothrombotic state; vasoconstriction & arterial stiffening Ischemia Advanced Glycation End Products: The body “glycates” end products of glycolysis, which means that some end products have a carbohydrate added to them AGE’s bind cellular receptors inducing inflammation, vascular permeability, procoagulant activity & monocyte influx Polyol Pathway (i.e. sorbitol & fructose) Excess glucose is converted to sorbitol, which accumulates in cells ↑ Oxidative stress ↑ Free Radical Formation Nerve hypoxia & impaired repair mechanisms leading to dysfunction & loss of peripheral nerves Distal motor axonal loss Abbreviations: AGE – Advanced Glycation End Products IGF - Insulin-like Growth Factor VEGF - Vascular Endothelial Growth Factor PKC – Protein Kinase C Autonomic neuropathy Large myelinated fibers Altered proprioception Atrophy of intrinsic foot muscles Fissures in skin of weight-bearing areas Infection & chronic ulceration Imbalance between toe extensors & flexors Weight shift results in pressure points Gastroparesis Claw toe deformity Erectile dysfunction X-ray: destruction of weight-bearing foot joints Loss of vibratory sensation in glove & stocking pattern distribution Charcot Foot Cardiac: Resting tachycardia, exercise intolerance, orthostatic hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com

Open Fractures

Open Fractures: Mechanisms, clinical features and complications Direct, high-energy force (e.g. vehicle collisions, gunshot) or low-energy force on diseased bone Force applied to bone exceeds strength of bone resulting in periosteal stripping and subsequent soft tissue and neurovascular destruction Open Fractures Also known as “compound fractures” and classified with the Gustilo-Anderson classification system (Types I, II, III), these are fractures in which the skin is penetrated and bone is exposed to the external environment. Comminuted fractures have ≥ 2 breaks in the bone. Inside-out (bone) or outside-in (external) penetration of skin to create a wound Skin tearing creates vacuum-like effect pulling debris into wound Minimal comminution Bone penetrates skin to create a wound < 1 cm in diameter (Type I) Smaller wound creates minimal opportunities for pathogen entry and contamination Moderate comminution Bone penetrates skin to create a wound 1-10 cm in diameter (Type II) Moderate wound creates some opportunity for pathogen entry and contamination Extensive comminution Bone penetrates skin to create a wound > 10 cm in diameter (Type III) Large wound creates ample opportunity for pathogen entry and extensive contamination Type IIIA (adequate soft tissue for bone coverage) Type IIIB (soft tissue damage with periosteal stripping) Type IIIC (vascular injuries, potential amputation) Displacement/shortening/ angulation/rotation of fracture fragment Improper bone healing Bone deformity Authors: Meaghan MacKenzie Holly Zahary Loreman Nojan Mannani Reviewers: Annalise Abbott Usama Malik Michelle J. Chen Dr. Prism Schneider* Dr. Jared Topham* * MD at time of publication Pain & lack of mechanical load bearing axis Inability to weight bear Decreased mobility promotes stasis of venous blood flow & intravascular vessel wall damage Deep vein thrombosis Potential progression to pulmonary embolism Bleeding or inflammation within fascia Muscle atrophy Compartment syndrome (↑ pressure in muscle) ** Open wound exposes bone Infiltration of debris & contaminants Infection of soft tissues or bone (osteomyelitis) Initial injury damages blood vessels Initial injury damages nerves ↓ Sensation distal to injury ↓ Limb function & proprioception ↓ Pulses distal to injury Amputation ↓ Blood flow to bone Avascular necrosis (bone tissue death) Limb ischemia ↓ Blood flow & oxygen delivery to tissues Compartment syndrome** Delayed union (bone healing) on serial radiographs Non-union (bone fails to heal) on serial radiographs **See corresponding Calgary Guide slide on Acute Compartment Syndrome Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 16, 2017; updated Nov 21, 2024 on www.thecalgaryguide.com

Statins Mechanisms and Side Effects

Statins: Mechanisms & side effects Activation of inducible nitric oxide synthase, in endothelial cells, systemically ↑ Nitric oxide ↑ Vasodilation Competitive inhibition of HMG-CoA reductase activity (rate controlling enzyme of cholesterol production) ↓ Mevalonate acid (cholesterol precursor) production in the mevalonate pathway (metabolic processes that produce cholesterol) ↓ Cholesterol ubiquinone (CoQ10) production ↓ Ubiquinone (protective of cellular oxidative effects) Impaired mitochondrial function ↓ Cyclooxygenase-2 (COX2) expression (enzyme involved in the production of prostaglandins) ↓ Availability of arachidonic acid (derivative of LDL cholesterol breakdown) ↓ Thromboxane A2 (lipid with prothrombotic properties) ↓ Platelet adhesion ↓ Thrombogenicity (tendency to generate blood clots) Improved endothelial function Improved myocardial blood flow ↓ Intrinsic cholesterol biosynthesis in the liver Compensatory mechanisms ↓ Isoprenoid production (electron & proton carriers) ↓ Isoprenoid intermediates ↓Inflammatory signaling proteins ↓Proliferation of macrophages ↓ Inflammation Upregulation of hepatic LDL receptors ↑ Hepatic LDL uptake ↓ Serum low-density lipoprotein (LDL) ↑ Apolipoprotein A1 (component of HDL) production ↑ High-density lipoprotein (HDL) Carries serum cholesterol back to liver ↓ Serum apolipoprotein B levels (acts as a tag for LDL, facilitating uptake by LDL receptors) ↑ Oxidative Stress Hepatocyte damage & inflammation ↑ Serum liver enzymes Hepatotoxicity ↓ ATP ↓ Serum cholesterol ↓ Muscle membrane stability Rhabdomyolysis (muscle breakdown) Author: Rupali Manek, Andrew Wu, Rafael Sanguinetti, Luiza Radu Reviewers: Joshua Dian, Laura Byford-Richardson, Alexander Ah-Chi Leung* * MD at time of publication Stabilization of plaques ↓ Atherosclerosis (plaque build-up in arteries) ↓ Coronary events & mortality Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Physiological outcome Published Jan 9, 2017; updated Nov 22, 2024 on www.thecalgaryguide.com

Hypocalcemia Pathogenesis

Hypocalcemia: Pathogenesis Malnutrition ↓ Oral intake Acquired (e.g. neck surgery) Autoimmune (e.g., autoimmune polyglandular syndrome) Infiltrative (e.g., hemochro matosis, Wilson’s disease) Congenital (e.g., DiGeorge) Hypomagnesemia Magnesium is needed to produce PTH Malabsorption ↓ Small bowel surface area ↓ Absorption of 25-OH Vitamin D (calcidiol) ↓ Conversion of calcidiol to 1-25 (OH)2 Vitamin D (calcitriol) by 1-α- hydroxylase ↓ Calcitriol (impacts GI absorption of calcium) Chronic Renal Failure ↓ Renal parenchymal mass (site of 1-α- hydroxylase production) Vitamin D Dependent Type 1 Rickets Mutation in the gene that encodes 1-α- hydroxylase ↓ Sun exposure ↓ 1-α-hydroxylase Pancreatitis Destruction or atrophy of parathyroid gland ↓ Parathyroid hormone (PTH) Calcitriol resistance (e.g., Vitamin D Type 2 rickets) Inflammation of pancreas ↑ Release of lipase enzyme into serum ↑ Breakdown of fat by lipase ↑ Free fatty acids in serum ↑ Ca2+ binding to negatively charged tail of free fatty acids ↑ Parathyroid hormone (PTH) PTH resistance Genetic mutation causes body to not respond to PTH ↓ Renal calcium reabsorption ↑ Calcium excretion ↓ Osteoclast activity ↓ Calcium release from bone ↓ Action of PTH on intestinal cells ↓ Absorption of calcium in the small intestine ↑ Serum phosphate (PO4) (e.g. tumor lysis, rhabdomyolysis) ↑ Ca2+ binding to negatively charged PO4 ↑ Serum pH ↓ H+ in serum binding to proteins ↑ Ca2+ binding to proteins Calcium sequestration ↓ Absorption of calcium in the small intestine Hypocalcemia Author: Breanna Fang Reviewers: Gurreet Bhandal, Raafi Ali, Luiza Radu Samuel Fineblit* * MD at time of publication Serum calcium levels below 2.10mmol/L Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 22, 2024 on www.thecalgaryguide.com

Acquired Inguinal Hernias

Acquired Inguinal Hernias: Indirect & Direct Abdominal fluid or mass Constipation Pregnancy Chronic cough ↑ intraabdominal pressure Stretching of musculoaponeurotic structures & weakening of the abdominal fibromuscular tissue Direct Inguinal Hernia Authors: Adam Bubelenyi Jeffery Lindgren Peter Bishay Reviewers: Sophia Khan Shahab Marzoughi Brandon Hisey Vadim Iablokov Usama Malik Dr. Sylvain Coderre* * MD at time of publication Developmental Ehlers-Danlos & Marfan syndrome (genetic disorders characterized by impaired connective tissue development) Collagen deficiency ↑ Protease activity Smoking Aging Malnutrition Collagen breakdown Long-term glucocorticoid use Fibroblast (cells which produce collagen) suppression causing ↓ collagen production Thinning of skin & soft tissues Incomplete obliteration of the processus vaginalis (peritoneal tunnel through which the testes migrate toward the scrotum during embryological development) Failed closure leaves an opening for organs to herniate through Intestinal loops entrapped within herniation Weakening of connective tissues Indirect Inguinal Hernia Protrusion of abdominal and/or pelvic contents through deep inguinal ring Protrusion of abdominal and/or pelvic contents through the Hesselbach triangle (anatomic area defined by the rectus abdominis medially, inferior epigastric vessels laterally, and the inguinal ligament inferiorly) Herniated contents become entrapped Inguinal mass +/- pain that is worse with straining Abdominal distension & tenderness Rhythmic contractions of the intestine attempting to push contents past the blockage site Colicky pain Incarceration (Surgical Emergency) Reduced vascular supply to entrapped contents Strangulation (Surgical Emergency) Constriction & ischemia of hernial contents Gangrenous skin changes (swelling, blue/purple colour, ↑ temperature, ulceration, ↓ sensation) Inflammation of the herniated contents to larger than the hernial opening Irreducible hernia (a hernia which cannot be manually reduced) Bowel Obstruction (Surgical Emergency) Obstruction of intestinal lumen impairs passage of intestinal contents Stimulation of stretch receptors in the bowel wall Nausea +/- vomiting Herniated tissue undergoes necrosis (irreversible cell death), perforating the gastrointestinal wall Obstipation (complete inability to pass stool or gas) Bowel perforation (surgical emergency) Leakage of gastrointestinal contents allows bacteria to infect the abdominal cavity Sudden ↑ pain Abscess (localized collection of pus) Peritonitis (inflammation of the peritoneum) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jun 3, 2018; updated dec 29, 2024 on www.thecalgaryguide.com

Barretts Esophagus

Barrett’s Esophagus: Pathogenesis, clinical findings and complications Gastroesophageal Reflux Disease (GERD) Authors: Sophia Khan Reviewers: Claire Song Shahab Marzoughi Sylvain Coderre* * MD at time of publication Reflux of stomach acid, bile salts + digestive enzymes through lower esophageal sphincter (located at junction between esophagus and stomach) Chronic reflux exposure to squamous epithelium (cells lining distal esophagus) Squamous epithelial cells release inflammatory cytokines: interleukin-8 and interleukin-1beta Inflammation of squamous epithelium Adaptive changes of squamous epithelium to prevent damage by acidic reflux Migration of stem cells in gastric cardia (proximal region of the stomach) into distal esophagus Replacement of esophageal squamous epithelium by gastric columnar epithelium Conversion (metaplasia) of normal esophageal squamous epithelium into abnormal gastric columnar epithelium with interspersed goblet cells Z line (the squamocolumnar junction between the esophagus and stomach) is irregular and displaced proximally on esophagus on endoscopy Heartburn (retrosternal burning sensation from stomach reflux) Regurgitation (involuntary expulsion of stomach content back into esophagus) Development of goblet cells (intestinal mucus-producing cells) within esophageal epithelium Abnormal presence of goblet cells on histology of distal esophagus Abnormal presence of columnar epithelial cells on histology of distal esophagus ↑ Atypical proliferation & ↓ apoptosis of Barrett’s epithelial cells Dysplasia (disordered growth of cells with the potential to develop into cancer) of Barrett’s epithelium Esophageal adenocarcinoma Improper division of nuclear chromatin (packaged DNA) Cellular nuclei increase in size due to retained chromatin from improper division Excess chromatin absorbs more stain during histology Double- stranded DNA breaks Nuclear enlargement on histology Continued acidic reflux causes oxidative DNA damage Hyperchromatic (darkly stained) nuclei on histology Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 15, 2024 on www.thecalgaryguide.com

Malignant Esophagitis

Malignant Esophagitis: Pathogenesis and Clinical Features Authors: Hamza Kamran Reviewers: Claire Song Shahab Marzoughi Sylvain Coderre* * MD at time of publication Barrett’s Esophagus (pre-malignant condition) Chronic gastric reflux (acidic partially- digested stomach contents) Conversion of normal esophageal squamous epithelium to metaplastic columnar epithelium Gastroesophageal Reflux Disease Recurrent regurgitation of gastric content Chronic Irritation & damage to the esophageal mucosa Lesions and plaques develop in distal esophagus Malignancy develops in the mucus-producing glandular cells in the lower esophagus Smoking Carcinogenic tobacco condensate is swallowed Irritation of the the esophageal lining Heavy alcohol consumption Mutation in alcohol- dehydrogenase, which breaks down ethanol ↓ Alcohol breakdown Irritation of the esophageal mucosa & lining ↑ Inflammation of the squamous epithelium located in the upper & middle esophagus Achalasia (Esophageal smooth muscle motility disorder) Food stasis in the esophagus ↑ Bacteria production Lactic acid production & fermentation damages esophageal mucosa Chronic inflammation in the esophageal epithelium Malignant cells invade the aorta & tracheobronchial region ↑ Spread & growth of cancer in other organ systems Metastatic invasion into the aorta, lungs, liver, bones, & kidneys through the lymph nodes ↑ Spread & growth of cancer in other organ systems ↑ Metabolic demand Unintentional weight loss Generalized chest pain Hoarseness Cough Esophageal adenocarcinoma (malignancy of the glandular cells of the esophagus) Esophageal squamous cell carcinoma (malignancy of the squamous epithelium of the esophagus) ↑ Metabolic demand ↑ Weight loss Chronic GI bleeding Iron-deficiency anemia ↑ Ulceration Exposure to stomach acid ↑ Tumor- induced inflammation ↑ Fibrosis Irregular stricture of the upper & middle esophagus Dysphagia Esophageal wall narrowing Abnormal reflexes of GI tract Dysphagia Indigestion Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 15, 2024 on www.thecalgaryguide.com

Pituitary Tumour Classification and Clinical Outcomes

Pituitary Tumour: Classification and clinical outcomes Functional tumour: Secretes excess Non-functional tumour (30%) (lack of hormone-producing cells or due to gene mutations) Authors: Chris Oleynick Caroline Kokorudz Reviewers: Amyna Fidai Laura Byford- Richardson Joseph Tropiano Julia Gospodinov Luiza Radu Hanan Bassyouni* * MD at time of publication hormones (70%) Relative abundance & predisposition for lactotroph (prolactin-producing), somatotroph (growth hormone – producing), thyrotroph (TSH producing) & corticotroph (adrenocorticotropic hormone – producing) cells to form adenomas (epithelial cell tumours) ↑ Lactotroph cells ↑ Prolactin (PRL) (most common) Hyper- prolactinemia (high prolactin blood levels) ↑ Somatotroph cells ↑ Growth hormone (GH) Acromegaly* (excess tissue growth & metabolic dysfunction) ↑ Corticotroph cells ↑ Adrenocortico- tropic hormone (ACTH) Cushing disease* (prolonged exposure to excess cortisol) ↑ Thyrotroph cells ↑ Thyroid stimulating hormone (TSH) Central hyper- thyroidism (↑ T4 & T3) Large size (macro) (>10mm on MRI) may cause mass effect (tissue compression from mass) Small size (micro) (<10mm on MRI) unlikely to cause mass effect (compression to surrounding structures) Asymptomatic Headache Nausea & vomiting Compresses pituitary gland & impairs blood supply & function of pituitary cells Impinges pituitary stalk & disrupts hormone transport from hypothalamus to the anterior and posterior pituitary Compresses surrounding structures ↑ Pressure & stretching of dural mater Stretching of the meninges activates mechanoreceptors (stretch receptors) in GI tract Pituitary hormone deficiency (typically in left-right order with mass effect): Dopamine release obstruction ↓ Inhibition of prolactin secretion Antidiuretic hormone (ADH) obstruction Inferior tumour growth Growth into sphenoid sinus Lateral growth of the tumor compresses surrounding cranial nerves Superior tumour growth ↓ GH ↓ Protein production & muscle cell proliferation ↓ Luteinizing hormone (LH) (triggers ovulation & sex hormone synthesis) & follicle stimulating hormone (FSH) (stimulates ovarian follicles & sperm growth) ↓ (TSH) ↓ ACTH (stimulates cortisol & androgen release) Cranial nerve (CN) II (optic) ↓ Visual acuity Diplopia (double vision) CN III, (oculomotor) IV (trochlear), or VI (abducens) Ptosis* (drooping upper eyelid) CN V (trigeminal) branches V1 & V2 Facial numbness Ophthalmoplegia (eye muscle paralysis) Compresses optic chiasma Bitemporal hemianopsia (decreased lateral peripheral vision) Tumour extends into hypothalamus Hypothalamic dysfunction due to damage to hypothalamic cells Disruption of multiple regulatory systems (i.e. sleep-wake cycles, appetite, temperature) Tumour occludes ventricles Tumour obstructs CSF flow ↑ Intracranial pressure Hydrocephalus* (abnormal buildup of CSF in ventricles of the brain) and papilledema Bacteria migrates from sinus flora into sphenoid sinus Cerebrospinal fluid (CSF) leaks into throat Post-nasal drip and nasopharyngeal mass Stunted growth and short stature in children ↓ Muscle mass & fatigue Diabetes insipidus* (excessive urination & extreme thirst) Central hypothyroidism* (↓ T4 & T3) Hyperprolactinemia Meningitis* (inflammation of the meningeal layers of central nervous system) *See relevant Calgary Guide slide Hypogonadotropic hypogonadism (↓ Sex hormones) Adrenal insufficiency* (↓ 8 AM cortisol) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 1, 2027; updated Jan 5, 2025 on www.thecalgaryguide.com

Central Precocious Puberty

Central Precocious Puberty: Pathophysiology in females Environmental/social causes Genetic conditions/mutation Neurocutaneous syndromes (multisystem conditions Neoplasms (including hamartomas), trauma, infection, ischemia Damage to hypothalamic & pituitary structures (i.e. infarct or traumatic sheering forces often causing inflammation and ultimately cell death) Septo-optic dysplasia (early brain development disorder) Abnormal pituitary & hypothalamus development (unknown pathogenesis) Psychosocial stress International adoption from developing countries Rapid increase in nutrition Rapid catch-up growth Hormonal and metabolic changes Endocrine disrupting chemicals (ex. Phthalates, bisphenol A) Hypothalamic inflammation Suppression of inhibitory and activation of stimulatory elements of the GnRH production pathway Idiopathic familial central precocious puberty from different genetic mutations primarily impacting tissues derived from ectoderm) Makorin RING- finger protein 3( MKRN3) mutation (repressor of GnRH secretion) Kisspeptin protein and/or receptor mutation (regulates puberty & reproductive function) Extended Kisspeptin protein availability and/or ↑ production Kisspeptin receptors signal directly to gonadotropin releasing hormone (GnRH) neurons to release GnRH into portal system Early ↑ or inappropriate GnRH pulses Neurofibromatos is T1 (NF1) (causes benign tumors to grow in the brain along nerves)* Tumor development involving the optic chiasm (>15% of individuals with NF1) may impact hypothalamic function Damage to and/or disruption of normal hypothalamic & pituitary function Tuberous sclerosis autosomal dominant disorder (rare genetic disease that causes growth of benign tumors in brain & body) Dysregulated cell division & growth Hamartomas form as benign mass composed of cells similar to those surrounding it, occurs in many areas including hypothalamic hamartoma (HH) HH acts as an accessory, unregulated hypothalamus Autonomous (unregulated) pulsatile GnRH release Sturge-Weber Syndrome (vascular disorder causing capillary-venus malformations impacting the face, brain, eyes) Vascular malformation throughout the brain including the hypothalamus Impaired blood flow to the hypothalamus Hypothalamic ischemia Hypothalamus dysregulation and premature activation of GnRH release Disruption of excitation and inhibition balance in the CNS Hypothalamic- pituitary dysregulation Reduced inhibition of GnRH secretion Increased corticotropin- releasing hormone Adrenal gland production & release of androgens by unknown mechanism that play a role in maturation of the HPG axis Adrenarche (start of androgen production). Including: acne, body odor, & pubarche (pubic hair growth) Dysregulated GnRH pulses Dysregulated luteinizing hormone (LH) & follicle simulating hormone (FSH) release Early GnRH release Early FSH secretion from pituitary gland ↑ Uterine volume & growth of ovarian follicles Cyclical ovulation Premature menarche (first menses < 7 years) Early LH secretion from pituitary ↑ Gonadal androgen production ↑ Estrogen release from ovaries gland **See Calgary Guide slide - “Brain Neoplasms” ↑ Skeletal growth ↑ Bone mineral density Thelarche (breast development) Authors: Joanna Keough Reviewers: Run Xuan (Karen) Zeng Luiza Radu Samuel Fineblit* *MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2025 on www.thecalgaryguide.com

Osgood Schlatter Disease

Osgood-Schlatter Disease: Pathogenesis and clinical findings Growth-related factors Anatomical variations that may ↑ risk Tibial tubercle develops as a secondary ossification centre, starting with a cartilaginous outgrowth Developing cartilaginous tibial apophysis has ↓ resistance to mechanical stress ↑ Susceptibility to injury prior to tibial apophysis and epiphysis fusion Adolescent growth spurt Longitudinal growth of tibia exceeds ability of quadriceps-patellar tendon unit to stretch ↓ Quadriceps flexibility Repetitive knee extensor mechanism activities during adolescence (eg. jumping, running) Patellar tendon inserts more proximally or broadly on tibia ↓ Patellar tendon moment arm length causes ↑ biomechanical forces on tibial tubercle Patella alta (superior displacement of the patella within the trochlear groove) *temporal relationship uncertain Quadriceps require ↑ forces to achieve full extension Patellar tendon overuse ↑ Patellar tendon tension ↑ Traction stress on the patellar tendon insertion at the cartilaginous tibial tubercle apophysis in one or both knees Osgood-Schlatter Disease Self-limiting osteochondrosis or traction apophysitis (inflammation of the growth plate) of the proximal tibial tubercle at the insertion of the patellar tendon Tibial tubercle apophysis hypertrophies & develops chronic micro-avulsions (tibial apophyseal ossification centers & cartilage is pulled off the tibial metaphysis) ↑ Inflammation at injury site Proximal patellar tendon micro- Repetitive strain/forces on the proximal tibial apophysis Tibial apophysis undergoes partial arrest Asymmetric proximal tibial epiphyseal growth abnormality (posterior > anterior) Genu recurvatum (knee hyperextension) (rare) due to traction apophysitis avulses from the tibial apophysis overcomes bone-tendon attachment strength Activated immune cells release cytokines at injury site Sensitization of nociceptors in periosteum and surrounding tissues Tenderness and Antalgic swelling of gait patellar tendon Proximal tibial apophyseal fragmentation (visible on X-ray) Avulsion fracture of tibial tubercle Calcium is abnormally deposited in the tendon Calcific tendinopathy in patellar tendon (visible on X-ray) Anterior knee pain that worsens with exercise Inflammatory mediators recruit osteoblast precursors to stabilize injury site ↑ Osteoblast activity drives bone remodeling and formation of ossicles (small pieces of bone) Bone remodeling causes united ossicles (ossicle fusion with tibial tuberosity) Ununited ossicle imbedded within patellar tendon (visible on X-ray) Bony prominence of tibial tubercle (visible on X-ray) Residual ununited ossicle remains after apophysis fuses with proximal tibial metaphysis Persistent visible prominence after proximal tibial apophyseal closure Authors: Emily J. Doucette Reviewers: Michelle J. Chan Yan Yu* Gerhard Kiefer* * MD at time of publication Persistent pain & discomfort with ↓ strength & function Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 16, 2025 on www.thecalgaryguide.com

Tonsillitis Pathogenesis and clinical findings

Tonsillitis: Pathogenesis and clinical findings Authors: Taylor Krawec Amanda Marchak Reviewers: Nicola Adderley, Jim Rogers Emily J. Doucette, Danielle Nelson* James D. Kellner* * MD at time of publication Pathogen infiltrates tonsillar epithelium Microfold cells recognize pathogen & activate immune response Virus (most common) Group A Streptococci (GAS) (most common bacteria) Group B, C & G Strep, Fusobacterium necrophorum Age 5-15 (tonsils have ↑ role in immune function at this age) Tonsillitis Inflammation of the tonsils Infectious agent exposure Susceptible host Pathogen colonizes the oropharynx Acute suppurative disease Immune cells release proinflammatory cytokines & antibodies Inflammatory mediators ↑ vascular permeability of tonsils Leakage of protein & fluid into surrounding tissue Regional nodes receive ↑ lymph Enlarged anterior cervical nodes Sinusitis** Pharyngitis** Local spread of pathogen Acute otitis media** Pneumonia** Cervical lymphadenitis Bacteria spread from tonsils into lymphatic system & bloodstream Bacteremia F. necrophorum invades lateral pharyngeal space & soft tissue in neck Thrombosis forms in peritonsillar vein Thrombosis extends into internal jugular vein Lemierre’s syndrome Systemic inflammatory cytokines disrupt hypothalamic regulation Fever Additional immune cells are recruited to facilitate immune response Macrophages phagocytize pathogen Bacteria invade distant tissue & elicit local inflammatory response Hepatitis Osteomyelitis Infective endocarditis Bacteria illicit systemic response Sepsis Tonsillar tissue become swollen & irritated Tonsillar hypertrophy Localized collection of pus forms Immune cells cause inadvertent cellular injury & hemolysis Palatal petechiae Meningitis Products of immune response & cellular debris are deposited into tonsillar tissue Peritonsillar or Tonsillar retropharyngeal abscess** exudate ** See corresponding Calgary Guide slide Toxin-mediated disease Bacteria release exotoxins into bloodstream Inflammatory mediators & cytokines are overactivated (cytokine storm) Skin has local inflammatory response Toxic shock syndrome** Scarlet fever** Post-infectious disease Antibodies to GAS cross react with host tissue Acute rheumatic fever** Post-strep glomerulonephritis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 5, 2018; updated Mar 14, 2025 on www.thecalgaryguide.com

Acute Infectious Mononucleosis

**See corresponding Calgary Guide slides Legend: Acute Infectious Mononucleosis: Pathogenesis & clinical findings Viral transmission (Epstein-Barr virus (EBV), Cytomegalovirus (CMV), human immunodeficiency virus (HIV), etc) through saliva (most commonly in adolescents & young adults aged 15-24) Virus infects epithelial cells of the oropharynx Virus infects & immortalizes circulating B lymphocytes Virus replicates in infected B-cells Immune cell proliferation in lymphatic system (primarily lymph nodes & spleen) Infected B-cells enter systemic circulation Systemic inflammatory response activated Inflammation & edema of sinuses Bilateral periorbital &/or palpebral edema Pharyngitis** (often with grey/white exudative secretions) Palatal petechiae Blood vessel damage in the soft palate Edema of soft palate & tonsils Airway obstruction ↑ Immunoglobulin M (IgM) antibodies to EBV viral capsid antigen (VCA) Positive IgM-VCA Immortalized B-cells produce ↑ antibodies Production of heterophile antibodies (weakly reactive & non-specific) Positive monospot (heterophile antibody) test (↓ sensitivity in children <4 years) Virus may remain dormant in B-cells Latent infection with periodic reactivation Generalized lymphadenopathy (enlarged lymph nodes) Massive cervical, mediastinal or hilar lymphadenopathy Posterior cervical lymphadenopathy Platelets sequestered (trapped) within spleen & overactive spleen (hypersplenism) discards ↑ platelets Thrombocytopenia (↓ platelets) Weak reticular tissue in the spleen stretches Splenomegaly Splenic rupture & becomes more susceptible to injury Inflammatory response ↑ energy demand Fatigue Longstanding impacts from unknown mechanism Chronic Fatigue Syndrome Inflammatory cytokines released into circulation ↑ Thermo-regulatory set-point at hypothalamus Fever Lymphocytosis (↑ lymphocytes) (markedly CD8+ T-cells & NK cells) Immune cells infiltrate the liver Hepatomegaly ↑ Aminotransferases Leukocytosis (↑ leukocytes) CD8+ T-cells & NK cells indirectly damage hepatocytes ↑ Bilirubin & jaundice** Systemic immune response &/or antibiotic hypersensitivity reaction CD8+ T-cells respond to virus Atypical lymphocytes on blood smear Generalized maculopapular rash Authors: Ayden Hansen, Griselle Leon Reviewers: Charissa Chen, Emily J. Doucette Danielle Nelson* * MD at time of publication Published Sept 3, 2015; updated Apr 22, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Trachoma

Trachoma: Pathogenesis and ocular manifestations Risk factors for infection Mode of transmission Authors: Palak Sharma, Helena Zakrzewski Reviewers: Prima Moinul, Riley Hartman Emily J. Doucette, Edsel Ing* * MD at time of publication Crowded living conditions Poor hygiene practices Limited access to sanitary facilities Direct contact with ocular & nasal secretions of infected individuals Indirect contact with fomites (contaminated objects or surfaces) Mechanical vectors: Eye-seeking flies (e.g. Musca sorbens) Chlamydia trachomatis infection (serotype A, B & C) Trachoma Chronic keratoconjunctivitis (inflammation of the conjunctiva & cornea) caused by recurrent infection with C. trachomatis Active Phase Bacteria infects the conjunctival epithelial cells Redness, irritation & mucopurulent discharge Immune response triggers inflammation of the upper tarsal conjunctiva Herbert’s pits (small, sunken scars at the limbus (border between cornea & sclera) from healed follicles Corneal lesions Pannus (invasion by superficial vessels) at the limbus Lymphoid follicles consisting mainly of B & T cells form in the upper tarsal conjunctiva Trachomatous inflammation - follicular: Presence of five or more white or yellow follicles, each 0.5 mm or bigger in size Inflammation leads to papillae formation with dilated blood vessels, infiltration of lymphocytes, plasma cells & neutrophils & proliferation of epithelial cells Small, raised bumps with a central blood vessel in the upper conjunctiva Papillary hypertrophy causes conjunctival thickening & opaqueness Trachomatous inflammation - intense: Papillae obscure deep tarsal blood vessels Repeated re-infection or untreated infections Cicatricial (scarring) Phase Proliferation of fibroblasts & deposition of collagen leads to scarring (fibrosis) Trachomatous scarring: White, horizontal lines or bands on upper tarsal conjunctiva Scarring blocks meibomian gland ducts Conjunctival epithelium atrophy & goblet cell destruction Subconjunctival fibrosis Entropion (eyelid turns inward) Cornea ulcers & scarring ↑ Tear evaporation ↓ Tear production Scar contraction distorts upper tarsal plate Dry eye Trachomatous trichiasis (eyelashes grow inward toward the eye) Corneal abrasion Corneal opacity & blindness Published Sept, 2 2015; updated May 7, 2025 on www.thecalgaryguide.com Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Meckels Diverticulum

Meckel’s Diverticulum: Pathogenesis and Clinical Findings No clear predisposition Stercolith (hard fecal mass) forms & is trapped in diverticulum Foreign body enters diverticulum & becomes trapped inside Incomplete vitelline duct obliteration (~5-7 weeks gestation) Diverticulum sags into Intussusception (section bowel lumen & acts as lead of intestine slides into Meckel’s Diverticulum point for intussusception adjacent region) Persistent remnant of vitelline duct containing all 3 layers of ileal mucosa (asymptomatic in 96-98% of cases) Diverticulum remains attached to umbilicus by persistent fibrous band Volvulus (loop of ileum twists around diverticulum) Ectopic tissue present within diverticulum Diverticulum goes through abdominal wall defect Littre’s Hernia (diverticulum in hernial sac) Diverticulum becomes incarcerated Ectopic gastric mucosa produces acid secretions Ectopic pancreatic tissue secretes digestive enzymes Ileal mucosa adjacent to diverticulum become ulcerated Inflammatory mediators disrupt hypothalamic regulation Small bowel becomes obstructed Perforation of diverticulum Brisk painless bleeding from small bowel Chronic inflammation & ulceration Fever Nausea/ vomiting Small bowel necrosis Hematochezia (bright red blood per rectum) ↓ Effective arterial blood volume Mucosa undergoes dysplastic & neoplastic transformation Complete erosion through ileal mucosa Small bowel perforation Hypotension Neuroendocrine tumour or other cancer Diverticulum becomes blocked & triggers local inflammatory response Meckel’s Diverticulitis Inflammation of Meckel’s Diverticulum Diverticulum is distended due to inflammation Visceral afferent nerves are stimulated by intestinal stretch Abdominal pain Chronic painless bleeding from small bowel Melena (partially digested blood in stool) Iron-deficiency anemia Authors: Taylor Krawec, Merry Faye Graff Reviewers: Emily J. Doucette, Sylvain Coderre* * Indicates MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Intestinal contents leak into peritoneum Peritonitis Systemic inflammatory response to peritonitis Published May 31, 2025 on www.thecalgaryguide.com Sepsis

Heparin-Induced Thrombocytopenia

Non-Immune Mediated: Type 1 (within two days of heparin administration) Platelets aggregate within the bloodstream ↓ Free unbound platelets in bloodstream Mild Thrombocytopenia: platelet count between 100 x 109/L - 150 x 109/L Fewer platelets available for thrombosis (formation of a pathological blood clot) Self limiting with no thrombotic risk Legend: Heparin-Induced Thrombocytopenia (HIT): Pathogenesis and clinical findings Obesity Hypertension Macrovascular disease Hyperlipidemia Heparin (often unfractionated) complexes with platelet factor 4 (PF4) on the platelet surface, due to heparin’s negative charge & PF4’s affinity for long-chain polysaccharides Immune-Mediated: Type 2 (within 5-15 days of heparin administration) Anti-heparin/PF4 Immunoglobulin G antibodies binds to the heparin-PF4 complex in the blood Splenic macrophages remove platelet- immunoglobulin G complexes in the spleen Thrombocytopenia: Platelet count < 100 x 109/L (though < 20 x 109/L should prompt consideration of other diagnoses) ↑ Vascular inflammation & endothelial dysfunction activate platelets Authors: Kelle Edgar, Hadi Hassan Sergio F. Sharif Reviewers: Haotian Wang, Jessica Asgarpour Yan Yu*, Lynn Savoie* Kareem Jamani* * MD at time of publication Activated platelets release PF4 Anti-heparin/PF4 antibodies activate adjacent platelets Activated platelets release inflammatory mediators Circulating anti- heparin/PF4 antibodies bind adjacent cellular targets Anti-heparin/PF4 antibodies bind endogenous heparan sulfate on endothelium Activated endothelium releases procoagulants thrombin & tissue factor Activated platelets release procoagulants (factors promoting blood clotting) Free platelets are consumed from formation of thrombi Hypercoagulable state (↑ risk of thrombosis) ↓ Platelets available to clot at different area of the body Thrombosis in coronary, peripheral or cerebral arteries Bleeding (rare) Myocardial infarction Acute ischemia Stroke Inflammatory mediators disrupt hypothalamic body thermoregulation Fever/ chills Inflammatory mediators promote vasodilation of arterioles under the skin ↑ Blood to surface of skin Flushing of skin Venous thrombosis in lower leg or lung Deep vein thrombosis Pulmonary embolism Microthrombi occlude vessels surrounding injection site, limiting nutrient supply Necrosis (tissue death) at heparin injection site Published Aug 29, 2014; updated Jun 16, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Varicella Zoster Virus

Varicella Zoster Virus (VZV) - Chicken Pox: Pathogenesis and clinical findings Exposure to individual with VZV infection VZV enters respiratory tract & conjunctiva VZV enters dendritic cells (DC) DCs travel to regional lymph nodes Primary viremia Authors: Morgan Garland, Sean Spence VZV replicates VZV proteins ↑ major ↓ MHCI Reviewers: in nasopharynx histocompatibility expression Yan Yu, Danny Guo, & CD4+ T cells complex class I on CD4+ T Emily J. Doucette, (MHCI) degradation cell surface Laurie Parsons*, James D. Kellner* *MD at time of publication Acute phase VZV evades the immune system VZV travels through the blood in CD4+ T cells Immune cells release cytokines to fight the virus (stronger in adults) Fluid & cellular debris accumulate between epidermal layers Generalized pruritic (itchy) vesicular rash at different stages of development (macule, papule, vesicle) Immune system activates & releases inflammatory compounds VZV replicates in liver, spleen & lymph nodes Erythema (redness) & pain Scratching lesions introduces bacteria Fibroblasts lay down collagen to heal skin lesions Resets thermostat in hypothalamus Systemic response Tissue damage in oropharynx Direct inflammation in neural tissues Cerebellar ataxia (more common in children) Bacterial superinfection from S. aureus & Streptococcus pyogenes (more common in children) Scarring Fever (prodromal) Malaise (prodromal) Sore throat (prodromal) Encephalitis (more common in adults) Abscess Cellulitis Toxic shock syndrome (TSS) Secondary viremia Immune cells release cytokines to fight infection (stronger in adults) Inflammation & fluid build up in lungs VZV travels through the blood in CD4+ T cells expressing skin homing receptors Fluid & cellular debris accumulate in damaged alveoli Lungs more susceptible to secondary bacterial infection Pneumonia** (more common in adults) VZV colonizes keratinocytes over several days VZV colonizes neurons & glial cells in the brain VZV colonizes alveolar epithelial cells Resolution & latency VZV tracks along neurons from sites of infection to dorsal root ganglia & cranial nerves ↓ MHCI expression in sensory ganglia Adaptive immune system controls viremia ↓ Viral gene expression Resolution of VZV infection & development of lifelong immunity Direct viral toxicity (DNA damage, mitochondrial dysfunction, & protein misfolds in infected cells) Apoptosis & dysfunction of infected cells Latent infection Stress or immune suppression may precipitate reactivation of VZV later in life Shingles** **See corresponding Calgary Guide slide Pathophysiology Mechanism Published Nov 12, 2012; updated Jun 22, 2025 on www.thecalgaryguide.com Legend: Sign/Symptom/Lab Finding Complications

Unconjugated Hyperbilirubinemia

Pre-hepatic causes of ↑ bilirubin production Pathologic Unconjugated Neonatal Hyperbilirubinemia: Pathogenesis and clinical findings Hemolytic disease of the newborn** Isoimmune- mediated hemolysis Rhesus (Rh) factor incompatibility Maternal sensitization against Rh-positive fetal cells Maternal antibodies against Rh factor attack fetal RBCs ABO incompatibility Native maternal antibodies against non- native blood types attack fetal RBCs Sepsis** Widespread systemic inflammation Cytokines & complement factors damage RBC membranes Disseminated intravascular coagulation** (clotting proteins become overactive) Clots form in systemic circulation Small clots shear & damage RBCs in circulation Red blood cell (RBC) enzyme defects Glucose-6 phosphatase dehydrogenase (G6PD) deficiency** G6PD protects RBCs against oxidative damage ↑ RBC sensitivity to oxidative stress (during acute stressors) Pyruvate kinase deficiency (PKD) Abnormal glycolysis & cellular energy production ↓ RBCs life spans RBC membrane defects Hereditary spherocytosis RBCs are abnormally round (spherocytes) RBC membranes easily damaged in circulation Bilverdin reductase Hereditary elliptocytosis RBCs are abnormally elongated or oval converts bilverdin to Sickle cell Abnormal hemoglobin (HbS) RBCs become abnormally unconjugated bilirubin disease** polymerizes under ↓ O2 sickle shaped Hemoglobinopathies Thalassemia's** Defective hemoglobin chains in RBCs Irregularly shaped RBCs trapped in spleen RBC sequestration ↑ Production of RBCs (Polycythemia**) Accumulation of blood (i.e. Cephalohematoma, hemorrhage) ↑ RBC load & turnover Causes of ↓ hepatocellular bilirubin clearance Genetic defects in uridine diphosphate glucuronosyltransfe rase (UGT) enzyme (conjugates bilirubin in liver) Gilbert syndrome Unconjugated bilirubin ↓ UGT production remains insoluble & cannot Crigler–Najjar be excreted in bile syndrome Type II Crigler–Najjar syndrome Type I No UGT production Breast milk jaundice Breast milk contains β-glucuronidase Causes of ↑ entero-hepatic bilirubin circulation Intestinal obstruction Obstruction blocks bile flow from liver to intestines Breastfeeding jaundice Inadequate milk intake (volume depletion/dehydration) ↑ Reabsorption of bilirubin in the intestines **See corresponding Calgary Guide slide Legend: Macrophages engulf old or damaged RBCs in spleen & liver ↑ Hemolysis (RBC breakdown) RBCs release cellular contents including heme (from hemoglobin) Heme oxygenase converts heme to bilverdin ↑ Unconjugated (indirect) bilirubin accumulation in blood ↑ Total serum bilirubin levels Excess bilirubin deposition into elastin- rich tissues (eg. skin, sclera) due to ↑ affinity for elastin Pathologic neonatal jaundice (yellow discoloration of skin within first 24 hours of life) Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 13, 2025 on www.thecalgaryguide.com Authors: Merry Faye Graff Khushi Arora Reviewers: Annie Pham Emily J. Doucette Danielle Nelson* * MD at time of publication Hemolytic anemia** ↓ Bilirubin conjugation β-glucuronidase deconjugates bilirubin Bilirubin builds up in hepatic system Unconjugated bilirubin crosses blood-brain barrier Bilirubin-induced neurologic dysfunction (BIND) Kernicterus (bilirubin- induced neurological damage) Scleral icterus (yellowing of sclera in eyes)

Lupus Muco-cutaneous Manifestations

Lupus: Muco-cutaneous Manifestations Drugs (procainamide, hydralazine, sulfa antibiotics) Environmental factors (ultraviolet radiation, chemicals, Epstein Barr virus infection) Estrogen and prolactin hormones at birth Cell damage reduces clearance of intracellular contents and disrupts tolerance of immune cells towards self-tissue Genetic predisposition (HLA-DR2 & HLA-DR3): Increased autoimmune disorders Authors: Heena Singh Kevin Zhan Reviewers: Bill Ressl Matthew Harding Luiza Radu Liam Martin* Glen Hazlewood* *MD at time of publication Other autoimmune diseases such as thyroid disorders and Sjorgen’s disease Scaring alopecia (hair loss with scarring) Antibodies bind self-antigens & form soluble immune complexes (ICx) that deposit and promote inflammation in joints, skin & kidney Circulating ICx cause vascular/muco- membranous changes ICx activate and use up complement to induce tissue damage ↓ Complement levels (C3/C4) in blood (proteins involved in immune response) **See corresponding Calgary Guide slide Legend: Mechanism B cells are activated to produce autoantibodies towards intracellular contents ↑ Anti-DNA antibodies (anti-Ro, anti-La, anti- Sm, anti-RNP) ICx stimulate Langerhan cells and keratinocytes to release cytokines which induce localized inflammatory response Subacute cutaneous lupus: scaly annular lesions and plaques form in sun exposed areas Red plaques with keratotic scaling that extend inflammation onto hair follicles resulting in follicular plugging Discoid rash (chronic, scaring) Ultraviolet light ↑ cell death of keratinocytes within the skin Abnormal removal by phagocytes ↑ local inflammation on skin ICx & immunoglobulin deposit at the dermal-epidermal junction (not restricted to mucous membranes) Mouth/nasal ulcers Inflammation destroys hair follicles through complex mechanism Alopecia** Vasospasm of blood vessels in skin dermal layer (↓ release and activity of nitric oxide on endothelium as a vasodilator ) & ↓ venous circulation Malar (butterfly) rash Photosensitivity Livedo reticularis (net-like blue skin discoloration) Vasculitis Raynaud’s phenomenon: white/blue/red discoloration of toes and fingers induced by stress and cold Pathophysiology Sign/Symptom/Lab Finding Complications Published May 23, 2013; updated Aug 12, 2025 on www.thecalgaryguide.com

Chronic Thromboembolic Pulmonary Hypertension CTEPH Pathogenesis

Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Pathogenesis History of ↑ hypercoagulability from ↑ plasma clotting factor VIII Impaired clot breakdown from fibrin being resistant to plasmin-mediated lysis Impaired angiogenesis from improper vascular endothelial growth factor function Inflammation from chronic conditions or infected medical implants Legend: ↑ Incidence & persistence of clots Splenectomy (etiology unknown) Pro-thrombotic & impaired healing state Fibrin clots embed into blood vessel walls of pulmonary vasculature Pulmonary vasculature undergoes cellular remodeling in response to remnant clots Hypoxia & growth factors drives smooth muscle proliferation Chronic growth factors trigger faulty angiogenesis in pulmonary vasculature Clots activate platelets to release platelet derived & vascular endothelial growth factors Clots activate T cells to release pro-inflammatory cytokines Interleukin-6 & tissue necrosis factor-α Cytokines activate macrophages to release transforming growth factor-β (TGF-β) TGF-β triggers fibroblasts to deposit extra cellular matrix (ECM) Abnormal cell proliferation narrows lumen & impairs vasodilation Chronic inflammation & ECM deposits cause vessel thickening & fibrosis Vascular obstruction & fibrosis ↓ pulmonary arterial cross-sectional area & ↑ vascular resistance CT pulmonary angiography shows pulmonary artery occlusions with clots, webs, & stenotic lesions ↑ Blood pressure in unoccluded vessels of the pulmonary vasculature causes pulmonary hypertension** ↑ Pulmonary vascular resistance reduces cardiac output, especially during exertion CTEPH (Chronic Thromboembolic pulmonary hypertension): Prolonged occlusion of the pulmonary arteries due to intraluminal fibrosis of thromboembolic material from unresolved PE clots Exertional dyspnea** (difficulty breathing with physical activity) Progressive ↑ right ventricular pressure causes right atrial dilation & right ventricle hypertrophy Echocardiogram shows enlarged right atrium & right ventricle Right heart failure** **See corresponding Calgary Guide Slide(s) Authors: Dinusha T. Senaratne Devansh Bhatt Reviewers: Midas (Kening) Kang Usama Malik Sergio Sharif Natalie Morgunov* Lian Szabo* Jonathan Liu* * MD at time of publication Published Feb 7, 2018; updated Aug 13, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Cystic Fibrosis

Authors: Navdeep Goraya, Spencer Montgomery Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Danielle Nelson* *MD at time of publication Reproductive Manifestations Incomplete development of Wolffian duct derivatives (vas deferens, epididymis, & seminal vesicles) Cystic Fibrosis (CF): Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (transmembrane chloride ion channel found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Inhibition of sperm transport (obstructive azoospermia) Male infertility Upper Respiratory Tract Manifestations Retained secretions in sinuses Failure to clear bacteria in sinuses Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Nasal polyps Chronic sinusitis Pancreatic Manifestations Trapped digestive enzymes degrade pancreatic tissue Pancreatic tissue damage triggers inflammation, scarring & fatty tissue replacement Islet cell damage & destruction Cystic-fibrosis related diabetes (CFRD) Lower Respiratory Tract Manifestations Retained secretions in airways Bacterial proliferation in lower airway Airway infection & inflammation Chronic productive cough Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** ↓ Production & secretion of pancreatic enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption Failure to thrive ↓ Absorption of fat-soluble vitamins Steatorrhea (↑ fat in stool) Vitamin D deficiency Vitamin K deficiency** Rickets** Osteoporosis** Coagulopathies Hepatic Manifestations Delayed passage of bile through biliary tree ↑ Loss of bile acids in stool Inflammatory hepatic response ↑ Production of lithogenic bile (bile supersaturated with cholesterol) Biliary cirrhosis with portal hypertension Cholelithiasis** Gastrointestinal (GI) Manifestations ↓ Movement of intestinal contents In newborns: Meconium ileus In children/adults: Distal ileal obstruction syndrome (DIOS) ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates **See corresponding Calgary Guide slide Legend: Sign/Symptom/Lab Finding Complications Pathophysiology Mechanism Published Jan 21, 2013; updated Aug 20, 2025 on www.thecalgaryguide.com Reproductive Manifestations Degeneration of Wolffian duct derivatives (vas deferens, epididymis, & seminal vesicles) Inhibition of sperm transport (obstructive azoospermia) Male infertility Cystic Fibrosis (CF): Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Authors: Navdeep Goraya, Spencer Montgomery Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Danielle Nelson* *MD at time of publication Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Upper Respiratory Tract Manifestations Retained secretions in sinuses Failure to clear bacteria in sinuses Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Nasal polyps Chronic sinusitis Lower Respiratory Tract Manifestations Retained secretions in airways Bacterial proliferation in lower airway Airway infection & inflammation Chronic productive cough Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** Pancreatic Manifestations Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption ↓ Absorption of fat-soluble vitamins Failure to thrive ↓ Serum Vitamin D Osteoporosis** Trapped digestive enzymes degrade pancreatic tissue Tissue damage triggers inflammation, scarring & fatty tissue replacement Islet cell destruction Cystic-fibrosis related diabetes (CFRD) Hepatic Manifestations Delayed passage of bile through biliary tree Inflammatory hepatic response Cirrhosis** & portal hypertension Gastrointestinal Manifestations ↓ Movement of intestinal contents In newborns: Meconium ileus In children/adults: Distal ileal obstruction syndrome (DIOS) ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications **See corresponding Calgary Guide slide Published January 21, 2013 on www.thecalgaryguide.com Please only review slide 1 – slides 3-7 are previous draft versions. Thank you! Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Name Name* *MD at time of publication In the vas deferens in utero Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Degeneration of vas deferens, Wolffian ducts & associated structures Infertility in affected males In upper respiratory tract Retained secretions in sinuses Failure to clear bacteria in airways Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Chronic sinusitis Nasal polyps In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Airway infection & inflammation Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption ↓ Absorption of fat- soluble vitamins Failure to thrive ↓ Serum Vitamin D Osteoporosis** Trapped digestive enzymes degrade pancreatic tissue Tissue damage triggers inflammation, scarring & fatty tissue replacement Islet cell destruction Cystic-fibrosis related diabetes (CFRD) In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis** & portal hypertension In GI tract ↓ Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery*, Name Name* *MD at time of publication In the vas deferens in utero Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Secretions accumulate in secretory passages throughout the body Degeneration of vas deferens, Wolffian ducts & associated structures Infertility in affected males In upper respiratory tract Retained secretions in sinuses Failure to clear bacteria in airways Persistent neutrophilic inflammation triggers tissue remodeling & mucosal overgrowth Bacterial proliferation Chronic sinusitis Nasal polyps In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Airway infection & inflammation Signs of obstructive lung disease (lung hyperinflation on x-ray & abnormal pulmonary function tests) Bronchitis ± bronchiectasis** Trapped digestive enzymes degrade pancreatic tissue Inflammation Scarring & fatty tissue infiltration Islet cell destruction Type II Diabetes Mellitus** In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat & protein malabsorption ↓ Absorption of fat- soluble vitamins Failure to thrive ↓ Serum Vitamin D Osteoporosis** In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis** & portal hypertension In GI tract ↓ Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com In the vas deferens in utero Retained secretions in sinuses Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Mutated CFTR proteins prevent Cl- reabsorption in sweat glands ↑ Secretion of Cl- into sweat ↑ Sweat Cl- concentration Mutated CFTR proteins in duct epithelial tissue of other parts of the body prevent diffusion of Cl- into secretions ↓ Cl- diffusion into peri-ciliary fluid ↓ Water composition of peri-ciliary fluid ↓ Clearance of mucociliary secretions Accumulation of secretions in secretory passages throughout the body obstructing these passages Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery* *MD at time of publication Degeneration of vas deferens, Wolffian ducts & associated structures Infertility in affected males In upper respiratory tract Failure to clear bacteria in airways Bacterial proliferation Chronic sinusitis Nasal polyps In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Airway infection & inflammation Signs of obstructive lung disease i.e. lung hyperinflation on x-ray & abnormal pulmonary function tests Bronchitis ± bronchiectasis Trapped digestive enzymes degrade pancreatic tissue Inflammation Scarring & fatty tissue infiltration Islet cell destruction Type II Diabetes Mellitus In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat and protein malabsorption ↓ Absorption of fat- soluble vitamins Failure to thrive ↓Serum Vitamin D Osteoporosis In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis & portal hypertension In GI tract ↓ Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑ Retention of meconium ↑ Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com In the vas deferens in utero Cystic Fibrosis: Pathogenesis, clinical findings, and complications Cystic Fibrosis Transmembrane Regulator (CFTR) autosomal recessive gene mutation on chromosome 7 CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) dysfunction Chloride channel no longer allows Cl- transport CFTR proteins in sweat glands reabsorb Cl- CFTR proteins in duct epithelial tissue of other parts of the body facilitate diffusion of Cl- into secretions ↓Reabsorption ↓Cl- diffusion into peri-ciliary fluid ↓Water composition of peri-ciliary fluid ↑Secretion of Cl- into sweat ↓Clearance of mucociliary secretions ↑Sweat Cl- concentration Accumulation of secretions in secretory passages throughout the body obstructing these passages Degeneration of vas deferens, Wolffian ducts & associated structures Authors: Spencer Montgomery, Navdeep Goraya Reviewers: Yan Yu, Kayla Nelson, Emily J. Doucette, Mark Montgomery* *MD at time of publication Infertility in affected males In upper respiratory tract Retained secretions in sinuses Nasal polyps Bacterial proliferation Chronic sinusitis In lower respiratory tract Chronic productive cough Retained secretions in airways Bacterial proliferation Signs of obstructive lung disease i.e. lung hyperinflation on x-ray & abnormal pulmonary function tests Airway infection & inflammation Bronchitis ± bronchiectasis Trapped digestive enzymes degrade pancreatic tissue Inflammation Scarring & fatty tissue infiltration Islet cell destruction Type II Diabetes Mellitus In pancreas Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat and protein malabsorption ↓Absorption of fat- soluble vitamins Failure to thrive ↓Serum Vitamin D Osteoporosis In biliary tree Delayed passage of bile Inflammatory hepatic response Cirrhosis & portal hypertension In GI tract ↓Movement of intestinal contents In children/adults: Distal ileal obstruction syndrome (DIOS) In newborns: Meconium ileus ↑Retention of meconium ↑Reabsorption of bilirubin Prolonged jaundice in neonates Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 21, 2013 on www.thecalgaryguide.com In the vas deferens in utero Degeneration of vas deferens, Wolffian ducts and associated structures Infertility in affected males Legend: Cystic Fibrosis: Pathogenesis, clinical findings, and complications Mutation of Cystic Fibrosis Transmembrane Regulator (CFTR) gene on chromosome 7 à Dysfunction of the CFTR protein (a transmembrane chloride ion channel that is found in exocrine tissue) Author: Spencer Montgomery Reviewers: Yan Yu, Kayla Nelson, Mark Montgomery* * MD at time of publication Chloride channel no longer allows Cl- transport In sweat glands, CFTR proteins are responsible for the reabsorption of Cl- In duct epithelial tissue of other parts of the body, CFTR proteins facilitate diffusion of Cl- into secretions Notes: • The CFTR mutation exhibits an autosomal recessive inheritance pattern • > 1700 different CFTR gene mutations are identified, ∆F508 mutation accounts for ~67% of cases in Caucasians. • Cystic fibrosis is diagnosed based presence of ↑ sweat chloride concentration, disease causing CFTR mutations, & symptoms of ≥ 1 associated organ system ↓ Cl- diffusion into peri-ciliary fluid → ↓water composition of peri-ciliary fluid In children/adults: Distal ileal obstruction syndrome (DIOS) ↓ reabsorption = ↑secretion of Cl- into sweat In GI tract ↓movement of intestinal contents ↓ clearance of mucociliary secretions In newborns: Meconium ileus ↑ retention of meconium → ↑ reabsorption of bilirubin Prolonged jaundice in neonates ↑ Sweat chloride concentration Accumulation of secretions in secretory passages throughout the body, obstructing these passages In biliary tree Delayed passage of bile → inflammatory hepatic response Cirrhosis & portal hypertension In upper respiratory tract In pancreas Trapped digestive enzymes degrade pancreatic tissue Nasal polyps Retained secretions in sinuses → bacterial proliferation Pancreas unable to secrete digestive enzymes into GI tract (pancreatic insufficiency) Fat and protein mal- absorption ↓ absorption of fat soluble vitamins Inflammation → scarring & fatty tissue infiltration → islet cell destruction Chronic sinusitis ↓ serum Vit. D Type II Diabetes Mellitus Failure to thrive Osteoporosis Published January 21, 2013 on www.thecalgaryguide.com In lower respiratory tract Chronic productive cough Retained secretions in airways → bacterial proliferation à Airway infection & inflammation Persistent respiratory tract infections Can progress to chronic bronchitis ± bronchiectasis (This is the biggest cause of death in CF) Pathophysiology Signs of obstructive lung dx: i.e. Lung hyperinflation (on x-ray), Abnormal pulmonary function tests Mechanism Sign/Symptom/Lab Finding Complications

Hypocalcemia Physiology

Hypocalcemia: Physiology Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis** or severe illness Authors: Serra Thai, Ryan Dion Reviewers: Jessica Hammal, Michelle J. Chen, Emily J. Doucette, Hanan Bassyouni* * MD at time of publication Parathyroid gland hypofunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge Syndrome) Impaired Mg-dependent generation of cyclic adenosine monophosphate ↑ Systemic inflammation ↑ Calcium sequestration into cells (mechanism of action unknown) ↓ Liver function & albumin synthesis ↓ Or inappropriately normal parathyroid hormone (PTH) in circulation ↓ PTH receptor (PTHR) sensitivity ↓ Albumin-bound calcium in blood ↓ PTHR signaling in kidneys ↓ PTHR signaling in osteoblastic lineage Vitamin D deficiency** (e.g. cells within bones ↓ intake, malabsorption) False hypocalcemia (↓ total serum calcium with normal Ca2+ levels) Acute pancreatitis** ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule Chronic kidney disease (CKD)** ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to active form) activity in kidneys ↑ Claudin14 (tight junction membrane proteins) expression in thick ascending limb (TAL) of the loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in distal convoluted tubule ↓ Nuclear factor kappa B ligand (RANKL) expression & binding to receptors on osteoclast precursor cells Pancreatic enzymes are prematurely activated ↓ Sodium reabsorption triggers electrochemical gradient changes ↓ Glomerular filtration due to ↓ kidney function ↓ Activated vitamin D (calcitriol) synthesis Claudin14 binds cation channels composed of Claudin16 & 19 in TAL tight junctions Lipase released from pancreatic autodigestion breaks down peripancreatic fat ↓ Renal phosphate filtration from blood ↓ Binding of vitamin D regulated calcium transporters in duodenum & jejunum Binding blocks paracellular Ca & Mg transport from tubule into vasculature through tight junctions ↓ Probability of calcium transport channels opening ↓ Osteoclast differentiation (responsible for breaking down bone) Free fatty acids bind ionized Ca2+ to form insoluble calcium soaps (saponification) ↓ Circulating ionized calcium in blood ↑ Phosphate-calcium crystal formation ↓ Gastrointestinal ↓ Renal reabsorption ↓ Bone resorption of calcium of calcium reabsorption of calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 23, 2025 on www.thecalgaryguide.com Hypocalcemia: Physiology Authors: Serra Thai Ryan Dion Reviewers: Jessica Hammal Michelle J. Chen Emily J. Doucette Hanan Bassyouni* * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) ↓ Parathyroid hormone (PTH) in circulation ↓ PTHR signaling in kidneys Chronic kidney disease (CKD) ↓ Renal blood flow ↓ Glomerular filtration ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate-calcium complex formation **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis** or severe illness Impaired Mg-dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ PTH receptor (PTHR) sensitivity ↑ Calcium sequestration into cells (unknown mechanism of action) ↓ Liver function Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to active form) activity in kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Synthesis of activated vitamin D (calcitriol) Claudin14 binds to cation channels composed of Claudin16 & 19 found ↓ Binding of vitamin D in TAL tight junctions regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca & Mg transport from tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium ↓ Synthesis of albumin ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression & binding to receptors on osteoclast precursor cells ↓ Osteoclast differentiation (responsible for breaking down bone) ↓ Bone resorption ↓ Albumin- bound calcium with normal free (biologically active) Ca levels False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Sign/Symptom/Lab Finding Complications Hypomagnesemia* Impaired magnesium- dependent generation of cyclic adenosine monophosphate ↓ PTH receptor (PTHR) sensitivity Hypocalcemia: Physiology Authors: Serra Thai Ryan Dion Reviewers: Jessica Hammal Michelle J. Chen * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis or severe illness ↓ Parathyroid hormone (PTH) in circulation ↓ PTHR signaling in kidneys Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to its active form) activity in the kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule Chronic kidney disease ↓ Sodium reabsorption ↓ Synthesis of activated vitamin D (calcitriol) ↓ Renal blood flow Electrochemical gradient changes Claudin14 binds to cation channels composed of Claudin16 & 19 found in TAL tight junctions ↓ Glomerular filtration ↓ Phosphate excretion ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca (and Mg) transport from the tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↑ Phosphate-calcium complex formation ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium *See corresponding Calgary Guide slide: “Hypomagnesemia: Physiology” ** See corresponding Calgary Guide slide: “Hypoca;cemia: Clinical Findings” Legend: ↑ Inflammation ↑ Ca sequestration into cells (unknown mechanism of action) ↓ Liver function ↓ Synthesis of albumin ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression and binding to its receptors on osteoclast precursor cells ↓ Differentiation of osteoclasts which are responsible for breaking down (resorbing) bone ↓ Bone resorption ↓ Albumin- bound calcium with normal free (biologically active) Ca levels False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Hypocalcemia: Physiology Authors: Serra Thai Reviewers: Jessica Hammal Michelle J. Chen * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis or severe illness Impaired magnesium- dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Parathyroid hormone (PTH) in circulation ↓ PTH receptor (PTHR) sensitivity ↑ Ca sequestration into cells (unknown mechanism of action) ↓ Liver function ↓ Synthesis of albumin ↓ PTHR signaling in kidneys Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to its active form) activity in the kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule Chronic kidney disease ↓ Sodium reabsorption ↓ Synthesis of activated vitamin D (calcitriol) ↓ Renal blood flow Electrochemical gradient changes Claudin14 binds to cation channels composed of Claudin16 & 19 found in TAL tight junctions ↓ Glomerular filtration ↓ Phosphate excretion ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca (and Mg) transport from the tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↑ Phosphate-calcium complex formation ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression and binding to its receptors on osteoclast precursor cells ↓ Differentiation of osteoclasts which are responsible for breaking down (resorbing) bone ↓ Bone resorption ↓ Albumin- bound calcium with normal free Ca levels due to homeostatic mechanisms False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Published MONTH, DAY, YEAR on www.thecalgaryguide.com **See corresponding Calgary Guide slide: “Hypomagnesemia: Physiology” Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Hypocalcemia: Physiology Hypomagnesemia** Authors: Serra Thai Reviewers: Jessica Hammal * MD at time of publication Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Vitamin D deficiency: ↓intake, malabsorption Pseudohypoparathyroidism Sepsis/severe illness ↓PTHR activation in kidneys CKD ↓ Renal blood flow ↓ Glomerular filtration ↓ Sodium- hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation **See corresponding Calgary Guide slide(s) Legend: ↓ 1-alpha hydroxylase enzyme activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Pathophysiology Mechanism Sign/Symptom/Lab Finding Impaired magnesium dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Parathyroid hormone (PTH) ↑ Claudin14 (tight junction membrane protein) activity in the thick ascending loop of Henle ↑ Binding of claudin14 to claudin16 Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↑ Calcium sequestration ↓ Liver function into cells (mechanism of action ↓ Synthesis of albumin ↓ PTH receptor remains (PTHR) sensitivity ↓ Albumin- unknown) bound calcium with normal ↓ PTHR activation in bones free Ca levels due to homeostatic mechanisms ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Osteoblast stimulation ↓ Nuclear factor kappa b ligand (RANKL) secretion ↓ Nuclear factor kappa b receptor (RANK) binding on osteoclast precursors cells ↓Osteoclast production ↓ Bone resorption False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2 <2.1mmol/L+]) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Complications Hypocalcemia: Physiology Hypomagnesemia** Authors: Serra Thai Pseudohypoparathyroidism Reviewers: Jessica Hammal * MD at time of publication Vitamin D deficiency: ↓ intake, malabsorption ↓ 1-alpha hydroxylase enzyme activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) CKD ↓ Renal blood flow ↓ Glomerular filtration **See corresponding Calgary Guide slide(s) Legend: Sepsis/severe illness Impaired magnesium dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Signaling proteins ↓ Parathyroid hormone (PTH) ↓ PTH receptor (PTHR) sensitivity ↑ Calcium sequestration into cells (mechanism of action remains unknown) Pathophysiology Mechanism ↓PTHR1 activation in kidneys ↓ Activation of G- coupled protein signaling pathways ↑ Expression of sodium-phosphate co-transporters (NaPiIIa & NaPIIc) in proximal tubule ↓ Expression & phosphorylation of transient receptor potential vanilloid (TRPV5, calcium transporter channel) in distal convoluted tubule ↓ PTHR1 activation in bones ↓ Osteoblast ↑ Claudin14 (tight stimulation junction membrane protein) activity in the thick ascending loop of Henle ↓ Nuclear factor kappa b ligand (RANKL) secretion ↑ Binding of claudin14 to claudin16 ↓ Nuclear factor kappa b receptor Inhibition of (RANK) binding on osteoclast ↓ Phosphate excretion Electrochemical ↓ Amount of claudin 16 & 19 gradient TRPV5 & ↓ from forming precursors cells changes probability of cation-permeable channels pores in the tight ↑ Phosphate opening junctions calcium ↓Osteoclast production complex formation ↓ Paracellular transport of calcium ↓ Renal reabsorption of calcium ↓ Bone resorption Published MONTH, DAY, YEAR on www.thecalgaryguide.com ↓ Liver function ↓ Synthesis of albumin ↓ Albumin- bound calcium with normal free calcium levels due to homeostatic mechanisms False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2 <2.1mmol/L+]) Sign/Symptom/Lab Finding Complications Hypocalcemia: Physiology Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Hypomagnesemia** Impaired magnesium dependent generation of cyclic adenosine monophosphate ↓ Parathyroid hormone (PTH) ↓ PTH sensitivity Vitamin D deficiency: ↓intake, malabsorption ↓ Enzyme 1-alpha hydroxylase activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Legend: ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↓ Transcription of calcium transporter genes in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ↑ Inflammation Authors: Serra Thai Reviewers: Jessica Hammal * MD at time of publication Sepsis/severe illness ↑ Calcium sequestration into cells ↓ Liver synthesis of albumin ↓ Albumin- calcium binding False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Levels of undigested fats in small intestine Free fatty acids percipitate calcium ↓ PTH receptor activation in bones ↓ Osteoblast stimulation ↓ RANKL ligand secretion ↓ RAANK receptor binding ↓Osteoclast production ↓ Bone resorption Hypocalcemia (serum [Ca2+] <2.1mmol/L) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Hypocalcemia: Physiology Vitamin D deficiency: ↓intake, malabsorption Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Hypomagnesemia** Impaired magnesium dependent generation of cyclic adenosine monophosphate ↓ Parathyroid hormone (PTH) ↓ PTH sensitivity ↓ Enzyme 1-alpha hydroxylase activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Legend: ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↓ Transcription of calcium transporter genes in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ↑ Inflammation Sepsis/severe illness ↑ Calcium sequestration into cells ↓ Liver synthesis of albumin ↓ Albumin- calcium binding False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Levels of undigested fats in small intestine Free fatty acids percipitate calcium ↓ PTH receptor activation in bones ↓ Osteoblast stimulation ↓ RANKL ligand secretion ↓ RAANK receptor binding ↓Osteoclast production ↓ Bone resorption Hypocalcemia (serum [Ca2+] <2.1mmol/L) Authors: Name Name Name Name* Reviewers: Name Name Name Name* * MD at time of publication Published MONTH, DAY, YEAR on www.thecalgaryguide.com Hypocalcemia: Physiology Chronic kidney disease ↓ Renal blood flow ↓ Glomerular filtration Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Vitamin D deficiency: ↓intake, malabsorption Sepsis/severe illness ↓ NHE3 activity and expression in proximal tubule ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle ↓ Parathyroid hormone (PTH) ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Enzyme 1-alpha hydroxylase activity ↓ PTH receptor activation in bones ↓ osteoblast stimulation ↓ RANKL ligand secretion ↑ Inflammation ↓ PTH sensitivity ↓ Glomerular filtration ↓ Liver synthesis of serum albumin False Hypocalcemia ↑ Calcium sequestration into cells** ↓ Lipase secretion from pancreas Acute pancreatitis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding ↓ Albumin- bound calcium Current mechanism is unknown ↑ levels of undigested fats in small intestine Complications Hypomagnesemia Multiple blood transfusions ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Inhibits claudin16 and 19 from forming cation permeable pores in the tight junctions ↓Probability of calcium transport channels opening ↓ Synthesis of activated vitamin D (calcitriol) ↓ RAANK receptor binding ↓ Calcium reabsorption ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9K, PMCa2B, NCX2) in the duodenum and jejunum ↓osteoclast production ↓ Bone resorption ↓ Serum calcium Hypocalcemia <2.1 mmol/L ↑ Precipitation of calcium by free fatty acids Authors: Name Name Name Name* Reviewers: Name Name Name Name* * MD at time of publication Published MONTH, DAY, YEAR on www.thecalgaryguide.com https://journals.physiology.org/doi/full/10.1152/physrev.00003.2004?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88- 2003&rfr_id=ori%3Arid%3Acrossref.org – Calcium Absoprtion across Epithelia https://academic.oup.com/endo/article-abstract/137/1/13/2498579 - PTH and Calcium Signaling Pathways https://www.pnas.org/doi/10.1073/pnas.1616733114 - Information on Claudin 14 https://onlinelibrary-wiley-com.ezproxy.lib.ucalgary.ca/doi/full/10.1111/apha.13959 - effects of PTH on renal calcium and phosphate handling https://www.ncbi.nlm.nih.gov/books/NBK430912/ - Hypocalcemia overview + causes + pathophys https://www.orthobullets.com/basic-science/9010/bone-signaling-and-rankl - information about bone signaling https://www.sciencedirect.com/science/article/abs/pii/S0889852921000682?via%3Dihub – Calcium homeostasis article https://pubmed.ncbi.nlm.nih.gov/3012979/#:~:text=Abstract,intestine%2C%20require%20the%20parathyroid%20hormone. vitamin D metabolism and function – https://pmc.ncbi.nlm.nih.gov/articles/PMC2669834/#:~:text=Calcium%20is%20actively%20absorbed%20from,for%20proper %20mineralization%20of%20bone. – more vitamin D metabolism and specific receptors https://jidc.org/index.php/journal/article/view/32903236/2331 - sepsis + hypocalcemia

Endometriosis

Endometriosis: Pathogenesis, clinical findings, & complications Risk factors Theories of endometrial tissue migration Genetic causes (family history & specific gene loci) Transfer of endometrial tissue away from the uterus during pelvic surgery, vaginal delivery, or cesarean section Sampson’s theory: Retrograde flow of endometrial tissue through fallopian tubes Long menstrual flows (↑ retrograde menstruation) Coelomic metaplasia theory: Undifferentiated mesothelial cells from the peritoneal cavity differentiate into endometrial cells during fetal development. May also occur in patients with testes Implantation theory: Menstrual endometrium implants onto pelvic structures ↓ Cellular antioxidant capacity (↑ cell damage) Alcohol use (mechanism unclear) Early menarche (↑ estrogen exposure) Stem cell theory: Endometrial stem/ Embryonic rest theory: Residual progenitor cells from menstrual embryonic cells from Müllerian Dissemination theory: Endometrial blood or neonatal uterine bleeding or Wolffian ducts are misplaced tissue transported through bloodstream implant in the pelvic cavity during organogenesis or lymphatics to extrauterine structures (e.g., brain, pericardium) Cells differentiate into endometrial-like tissue Ovary releases estrogen & progesterone Endometriosis Endometrial glands & stroma (structural support tissue) found outside the uterus Ectopic endometrial-like tissue on bladder Ectopic endometrial-like tissue in posterior cul-de-sac Monthly proliferation (by estrogen) and stabilization (by progesterone) of endometrial tissue Chronic inflammation of surrounding tissues & fibrosis/adhesion formation Tissue inflammation & fibrosis/adhesions push on & displace pelvic organs Ectopic tissue abnormally activates nerve signaling pathways responsible for bladder contraction Bladder wall contractions activate nociceptors (pain sensors) Penetrative intercourse involving the posterior vagina applies ↑ pressure to tethered & immobile pelvic structures Feces moves down colon into rectum & applies pressure to the tethered rectum Monthly progesterone withdrawal Dyspareunia (pain with deep intercourse) Dyschezia (pain with bowel movements) ↑ Urinary frequency & urgency Pain with micturition (urination) Endometrial tissue sloughs off from a basal tissue layer (menstruation**) Extra-uterine endometrial- like tissue cannot evacuate the implantation site Retrograde menstruation in ovary ↑ the presence of ectopic endometrial-like tissue & blood (mechanism poorly understood) Old blood fills endometrial-like tissue on ovary Endometrioma (chocolate cyst) Chronic cyclical local inflammation (release of pro-inflammatory chemicals) Nociceptors near ectopic endometrial-like tissue activate Pain signals & release of inflammatory mediators subsides over time Cyclic dysmenorrhea (menstrual pain) Repair of inflammation Ectopic endometrial-like tissue becomes fibrotic (scarred) Significant ↑ scar tissue Nodule formation ↓ Hormone levels post-menopause Accumulation of inflammatory fluid within scar tissue ↑ Risk of scar tissue obstructing or kinking fallopian tubes Endometrial tissue stops proliferating Hormone-dependent symptoms (e.g., dysmenorrhea) cease Cyst formation Embryos unable to pass through fallopian tube to uterus Author: Joshua Seto Kayla Nelson Reviewers: Yan Yu Sean Spence Jessica Revington Infertility Colin Birch*, Rachel Wang* * MD at time of publication **See corresponding Calgary Guide slide Legend: Published December 20, 2013, revised September 24, 2025 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Hydrocephalus in pediatrics

Aqueduct stenosis (channel between 3rd & 4th ventricle narrows) Narrowing blocks CSF flow from 3rd to 4th ventricle Congenital anomalies blocking CSF flow Atresia of foramen of Monro (channels connecting paired lateral ventricles & 3rd ventricle narrow) Narrowing blocks CSF flow from lateral ventricles to 3rd ventricle Posterior fossa malformations (4th ventricle closure failure) (e.g. Dandy-Walker Malformations) Persistence of Blake's pouch (cyst in 4th ventricle) obstructs CSF outflow from 4th ventricle Brain mass/tumor (e.g. medulloblastoma, pinealoma) Obstructs the passage of CSF from ventricles to subarachnoid space Hydrocephalus in Pediatrics: Pathogenesis and complications Intracranial or subarachnoid hemorrhage (brain bleed) Blood accumulates in ventricles or subarachnoid space Accumulated red blood cells break down over time & release hemoglobin, bilirubin, etc. Blood clots form in subarachnoid spaces & around ventricular outlets Developmental cysts (CSF filled sacs located between the brain & arachnoid Infection in brain membrane – e.g. tissue or meninges Arachnoid Cysts) (e.g., meningitis) Breakdown products trigger inflammation of ependymal lining & arachnoid membranes Immune cells respond to infection & accumulate Inflammation stimulates transforming growth factor- beta (TGF-β) & neutrophil extracellular traps (NETs) Exudate & pus form in subarachnoid spaces & around ventricular outlets TGF-β promotes fibrosis in subarachnoid space NETs obstruct meningeal lymphatic vessels Scarring & obliteration of arachnoid villi Obstruction impairs cerebrospinal fluid (CSF) drainage through lymphatics Choroid plexus tumors Choroid plexus epithelial cells are overactive Sacs compress or obstruct interventricular foramina, 3rd or 4th ventricle, aqueduct of Sylvius, etc. (location dependent) Congenital absence of arachnoid villi Impaired CSF resorption Normal flow of CSF is physically blocked Overactivity produces excessive CSF Communicating hydrocephalus (CSF accumulation due to impaired absorption or increased production in the subarachnoid spaces) Obstructive hydrocephalus (CSF accumulation due to structural blockage of CSF flow within the ventricular system) Hydrocephalus Active distension of the ventricles in the brain due to excessive accumulation of CSF Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 29, 2025 on www.thecalgaryguide.com Chiari II malformation (downward herniation of cerebellum, brainstem, & 4th ventricle through foramen magnum) Herniated structures block CSF outflow to spinal cord Authors: Abisola Adegbulugbe, Lexyn Iliscupidez Reviewers: Annie Pham, Merry Faye Graff, Emily J. Doucette, Jean Mah* *MD at time of publication Legend:

Reactive infectious mucocutaneous eruption

Reactive Infectious Mucocutaneous Eruption (RIME): Pathogenesis & clinical findings Bacterial or viral respiratory infection (most common infectious agent is Mycoplasma pneumoniae) ↑ Proliferation of polyclonal B cells (antibodies secreted by different B cell lines) & ↑ antibody production Antibodies cross-react (react to multiple antigens) with antigens in host tissue causing inflammation & tissue damage Systemic & local inflammatory response targets infectious agent RIME prodrome (early symptoms indicating a forthcoming illness) Fever Malaise Cough Dyspnea Inflammation & tissue damage activate inappropriate immune responses at distal sites Authors: Sonia Czyz Reviewers: Shahab Marzoughi Jessica Revington Michele Ramien* * MD at time of publication Normal Mucosa Complement system activates as part of the immune response & produces various complement proteins Epithelium Lamina propria Complement proteins C3a & C5a attract other immune cells to the site of infection & initiate ↑ inflammatory responses Complement protein C3b tags pathogens & infectious agents to help immune cells identify them ↑ Leukocyte infiltrate (accumulation) in tissue & ↑ vascular permeability of surrounding tissues Skin tissue experiences immune-mediated damage from immune cells & active complement proteins Cutaneous lesions (abnormal surface skin growths or skin changes) Mucositis in RIME Legend: Pathophysiology Mechanism Antibodies bind to antigens & form active immune complexes to attack infectious agents Immune complexes circulate in the body to target infectious agents. Antigen excess forms additional immune complexes Immunoglobulin G antibodies specific to the infectious agent cross- react with antigens on keratinocytes (keratin- producing skin cells) & mucosal cells in the epidermis (outermost skin layer) Additional immune complexes continue circulating in the absence of an infectious agent & subsequently deposit in skin tissue & mucous membranes Antibodies & immune complexes Leukocyte infiltrate Destructive inflammatory response induced at mucosal & skin sites with no target pathogen or infectious agent Complement activation Mucosal sites experience localized intense inflammation & ongoing immune-mediated damage from active complement proteins Severe mucositis (inflammation & ulceration of the mucous membranes) Acute hemorrhagic (excessively bleeding) crusts & erosions, ulcers, or vesiculobullous lesions (fluid-filled blisters) in multiple mucosal sites Published Nov 8, 2025 on www.thecalgaryguide.com Full-thickness epithelium necrosis (tissue death) Lamina propria Sign/Symptom/Lab Finding Complications Mucositis in RIME Reactive Infectious Mucocutaneous Eruption (RIME): Pathogenesis and clinical findings Normal Mucosa Epithelium Bacterial or viral respiratory infection; most common infection is Mycoplasma pneumoniae Systemic and local inflammatory response towards invading microbe Lamina propria Polyclonal B cell proliferation and antibody production Full-thickness epithelium necrosis Prodrome: cough, dyspnea, malaise, fever ~1 week prior to mucocutaneous eruption The antibodies cross-react with host tissue causing inflammation and tissue damage Lamina propria Authors: Sonia Czyz Reviewers: Shahab Marzoughi * MD at time of publication Inappropriate immune responses at distal sites Molecular mimicry Immune complex activation Complement activation I would remove all of this Immunoglobulin G antibodies specific for invading microbe cross- react with antigens on keratinocytes and mucosal cells in the epidermis Circulating immune complexes form in antigen excess C3a, C5a, and C3b produced Deposition in skin and mucous membrane ↑ Leukocyte infiltrate and vascular permeability Severe mucositis (inflammation and ulceration of the mucous membranes Destructive inflammatory response at mucosal and skin sites Antibodies & immune complexes Leukocyte infiltrate Complement activation Acute occurrence of hemorrhagic crusts and erosions, ulcers, or vesiculobullous lesions in 2 or more mucosal sites Localized inflammation and immune response activate complement system which damage mucosal tissues Immune response leads to painful, red nodules typically on the shins Triggering localized, intense inflammation and immune- mediated damage in these specific mucosal sites. Legend: Widespread systemic immune response Erythema nodosum Urticaria Immune response results in hives or itchy welts on the skin. Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Cutaneous lesions Published MONTH, DAY, YEAR on www.thecalgaryguide.com

Acute Tubular Necrosis

Acute Tubular Necrosis: Pathogenesis & clinical findings Severe systemic volume depletion (e.g., vomiting, diarrhea) Septic shock** Cardiogenic shock** Cholesterol embolization syndrome (rare) Severe hypotension ↓ Mean arterial pressure reduces renal perfusion pressure which ↓ renal blood flow Renal vascular autoregulation fails to maintain renal perfusion Tubular cell hypoxia & depletion of adenosine triphosphate (ATP) (primary energy carrier in cells) Cell ion pump failure, cell swelling, & cell membrane disruption Ischemic tubular necrosis (renal tubular cell injury secondary to ↓ blood flow) Myoglobinuria Hemoglobinuria Aminoglycosides Ethylene glycol Amphotericin Cisplatin ↓ Efficiency of kidney reabsorption & excretion Kidney removes ↓ potassium (K+) from the blood volume Hyperkalemia** (high K+ concentration in the blood) ↑ Serum K+ levels induce abnormal cardiac electrical conduction patterns & excessive cardiac excitability Fatal cardiac dysrhythmia (irregular heartbeat pattern) Kidney removes ↓ urea from the blood volume Kidney removes ↓ creatinine from the blood volume Azotemia (↑ serum urea & creatinine) Uremic toxins systemically impair neutrophil function Uremic toxins (indoxyl sulfate or paracresyl sulfate) induce oxidative stress in the brain through accumulation of reactive oxygen species (ROS) ↑ Risk of infection ROS damage neuronal membranes & ion channels & induce dysfunctional mitochondria in the brain Authors: Adam Bubelenyi Reviewers: Britney Wong Luiza Radu Jessica Revington Veronica Hammer* Braden Manns* * MD at time of publication **See corresponding Calgary Guide slide Dysfunctional brain mitochondria cannot properly metabolize purines & urea Brain cannot use any metabolic or cellular pathways requiring ATP ↓ Cerebral neuronal signaling Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Intravenous (IV) administration of iodinated contrast medium Tumor lysis syndrome Cancer cell apoptosis (cell death) releases ↑ uric acid & phosphate Heme-containing pigments Medications Uric acid & calcium phosphate crystals precipitate in renal tubules Nephrotoxic substances damage renal tubular cells through unique mechanisms Lipid peroxidation (oxidative degradation) of lipid bilayer weakens renal tubular cell membranes Damage to mitochondria in tubular cells causes depletion of ATP Formation of oxygen free radicals in renal tubular cells Impairment of ATP- dependent processes Activation of pro-inflammatory cytokines & enzymes in the kidney ↑ Renal tubular cell permeability Disruption of protein synthesis & enzyme function in renal tubular cells Degradation of tubular cell membrane lipids & proteins Free radicals oxidize tubular cell proteins & impair structure & function Toxic tubular necrosis (renal tubular injury due to nephrotoxic substances) Acute Tubular Necrosis Acute kidney injury via renal tubular cell damage & cell death Denudation (removal of surface tissue layers) & erosion of the tubular basement membrane Kidney removes ↓ sodium (Na+) & water from the blood volume ↓ Bicarbonate reabsorption from the proximal tubule of the kidney Necrotic tubular cells fall into tubular lumen Ongoing tubule damage ↓ ability to concentrate urine solutes ↓ Bicarbonate neutralization of acids in the blood Necrotic tubular cells release intracellular contents Obstruction of tubular lumen impedes glomerular filtration ↓ Urine osmolality (low urine solute concentration) ↑ Water in blood volume dilutes Na+ serum concentration Metabolic acidosis (blood pH <7.35) Muddy brown granular casts ↓ Glomerular filtration rate (GFR) Hyponatremia** (low Na+ concentration in the blood) ↑ Na+ retention in the circulatory blood volume & ↓ Na+ excretion in the urine ↓ Urine output Accumulation of ROS activates microglia & releases pro-inflammatory cytokines ↑ Fluid retention in the circulatory system Aggressive IV fluid rehydration in septic shock or cardiogenic shock patients Cerebral inflammation ↑ oxidative damage to neurons & glial cells Fluid overload Uremic encephalopathy Pulmonary edema (excess fluid accumulation in lung alveoli & interstitium) Published November 15, 2025 on www.thecalgaryguide.com Complications Disruption of DNA & RNA synthesis within renal tubular cells Tubular epithelial cells in urine Epithelial cell casts in urine (cast composed of epithelial cells embedded in a matrix) ↓ Ability to clear bacteria in urine ↑ Risk of urinary tract infection

Infection-Related Glomerulonephritis

Infection-Related Glomerulonephritis: Pathogenesis & clinical findings Viral or bacterial infections (most commonly streptococcus & staphylococcus) trigger the inflammatory cascade Common infection sites include pharyngitis (infection of the mucous membranes in the oropharynx) & endocarditis (inflammation of the endocardium) but bacterial infections can originate anywhere in the body In streptococcal infections, bacteria release nephritis (inflammation of the kidney) associated plasmin receptor antigens (NAPlr) & streptococcal pyrogenic exotoxin B antigens (SPeB) into the systemic circulation from the infection site. Other bacterial infections may have different pathophysiology Immune response generated against circulating NAPlr & SPeB antigens includes ↑ production of IgG antibodies (critical for immune response & memory) IgG antibodies bind with self-antigens (molecules recognized by the immune system as belonging to the host) including plasmin & glomerular proteins (proteins found in the kidney’s filtering unit, the glomerulus) IgG antibodies activate plasmin (enzyme responsible for breaking down protein in the kidneys) Plasmin degrades protein in the kidneys IgG antibodies bind to glomerular proteins in the kidney & form immune complexes in glomeruli basement membrane & sub- epithelial podocytes (highly specialized cells in the glomerular filtration barrier) Degradation of key glomerulus components, including the glomerular basement membrane (GBM) & mesangial matrix Damage to key glomerulus components leads to abnormal regulation of blood filtration ↓ Selective permeability of the glomerular membrane IgG antibodies bind with NAPIr & SPeB antigens & form immune complexes (antibody & antigen combinations involved in immune system signalling) Immune complexes circulate & deposit in glomeruli basement membrane & sub-epithelial podocytes RBCs escape through the glomerulus into renal tubules & progress into the urine Dysmorphic hematuria (blood in the urine characterized by misshapen RBCs) Author: Joanna Keough Reviewers: Britney Wong Luiza Radu Jessica Revington Veronica Hammer* Louis Girard* *MD at time of publication **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Immune complexes activate complement (C3, oxidizing agents, proteases) Complement activation helps ↑ proliferation of glomerular mesangial cells (cells with specialized proteins capable of producing motile forces) Mesangial cells produce extracellular matrix in the glomerulus Excess extracellular matrix blocks glomerular capillaries Mesangial cells release chemoattractants (signalling molecules) into the glomerulus & attract various immune cells Lymphocytes follow chemoattractants to the glomerulus & activate Neutrophils follow chemoattractants to the glomerulus & release lysosomal enzymes Lymphocytes accumulate in the glomerulus & obstruct glomerular capillaries Impaired blood flow through glomerular capillaries Capillary injury Podocyte injury or death Infection-Related Glomerulonephritis Glomerular kidney damage sustained after a bacterial or viral infection ↓ Glomerular filtration rate (GFR) Creatinine builds up in the blood ↑ Glomerular membrane permeability allows large molecules to pass through the membrane (e.g., red blood cells (RBCs), protein) ↓ GFR impairs the kidney’s ability to filter & excrete fluid ↓ Estimated GFR Prolonged (eGFR) renal damage Protein escapes into renal tubules & progresses into the urine Chronic kidney disease Proteinuria (loss of protein through the urine) ↑ Fluid retention in systemic circulation & ↓ renal blood flow Impaired potassium excretion ↓ Urine output Impaired acid waste product excretion Urine contains ↑ large proteins (e.g., albumin) Activation of the intrarenal renin- angiotensin-aldosterone system (RAAS)** Hyperkalemia (↑ serum potassium) Oliguria (↓ urine volume) Metabolic acidosis** Albuminuria (loss of albumin through the urine) Intrarenal RAAS activation leads to ↑ angiotensin II (Ang II) production ↑ Sodium & water retention in systemic circulation & ↓ excretion in urine (↓ GFR) Hypertension** Edema (swelling due to ↑ fluid in body tissues) Circulating blood volume exerts ↑ pressure on blood vessels & forces the heart to pump harder Left ventricle thickens & enlarges over time & demonstrates progressive cardiac injury (e.g., fibrosis, loss of cardiac muscle cells) Impaired cardiac output Heart failure Sign/Symptom/Lab Finding Complications Published November 15, 2025 on www.thecalgaryguide.com

Pyelonephritis

Acute Pyelonephritis: Pathogenesis and clinical findings Female sex Indwelling Diabetes (especially post- urinary catheter mellitus menopausal due to loss of protective Lactobacillus species) Obstruction of bladder outlet (congenital/acquired) High blood glucose damages nerves controlling the bladder, as well as blood vessels supplying bladder nerves Glycosuria (elevated levels of glucose in urine) create nutritive environment for bacterial growth Excessive urine buildup increases pressure exerted against the bladder, pushing urine from bladder up to ureters Authors: Sergio F. Sharif Reviewers: Michelle J. Chen Jessica Revington Yan Yu* Juliya Hemmett* Brandon Christensen* * MD at time of publication Shorter urethra allows for fecal microbes to more readily enter the urinary tract Catheter inoculates deep urinary tract with bacteria & facilitates organisms to enter bladder Neurogenic bladder (decreased bladder control due to nerve damage) is unable to appropriately release urine, leading to urinary retention & failure to clear residing bacteria Bacteremia (bacterial infection in bloodstream) Bacteria initially colonize the lower urinary tract, then migrate up the tract towards one or both kidneys (most commonly Gram-negative rods, e.g., Escherichia coli) Bacteria, such as Staphylococcus species, spread from another site of infection to kidneys via bloodstream Acute Pyelonephritis Inflammation of the kidney interstitium due to upper urinary tract infection, usually bacterial Collective contribution of mechanisms stated below, if severe Sepsis** Concurrent cystitis irritates urinary tract (see lower UTI slide)** Bacteria expressing virulence factors (e.g., P fimbriae in Escherichia coli) exploit host susceptibility & infect upper urinary tract (ureters & kidneys) Positive urine culture Dysuria (pain & burning while urinating) Bacteria trigger IL-8 release by local immune cells in the upper urinary tract, triggering recruitment of neutrophils to renal tubules & interstitium Neutrophils degranulate in the infected tissue, phagocytose bacteria & form sacrificial neutrophil extracellular traps (resulting in neutrophil death) in attempt to clear infection Neutrophil-mediated immune response damages surrounding kidney tissue (tubular injury) Acute kidney injury** Immune cells at the site of infection release cytokines (e.g., IL-1, TNF), which disseminate systemically Cytokines act in the brain in concert with unclear mechanisms relating to tissue injury & inflammation triggered by infection (see Neurotransmitters & Pharmacology behind Nausea and Vomiting slide**) Cytokines bind receptors in the anterior hypothalamus, triggering pathways ultimately leading to heat-generating responses (e.g., shivering) Cytokines promote the growth & release of white blood cells from bone marrow into bloodstream Dead neutrophils collect in renal tubules near infection & attach to assemblies of mucoprotein (a renal tubular epithelium protein secreted into tubules) Pyuria (WBCs in urine) Nausea/vomiting Fever Leukocytosis (↑ WBCs) Urine white blood cell (WBC) casts (cylindrical particles with WBCs seen on microscopy) Costovertebral Flank pain CT KUB - angle tenderness findings may include focal or diffuse involvement, fat stranding, gas formation, &/or other complications including renal scarring **See corresponding and abscesses Calgary Guide slide(s) Complications Published November 23, 2025 on www.thecalgaryguide.com Unclear mechanism involving systemic inflammation worsens mental status in susceptible individuals Altered level of consciousness (especially in elderly) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding

Hypothyroidism

Hypothyroidism: Pathogenesis & Clinical Findings Hashimoto’s thyroiditis Transient congenital hypothyroidism Congenital deficiency of thyroid hormone (TH) Iodine deficiency Infiltrative disease affecting thyroid gland cells Iatrogenic or medication- related thyroid dysfunction Hypothyroid phase of thyroiditis (inflammation of the thyroid) Pituitary gland dysfunction (central hypothyroidism) Progressive autoimmune destruction of thyroid gland cells ↓ T3/T4 levels activate the hypothalamus- pituitary-thyroid axis & ↑ TSH release by the pituitary gland Primary hypothyroidism (↑ TSH and ↓ T3/T4) ↓ T3/T4 levels cause ↓ expression of TH-dependent myocardial enzymes essential for cardiac contractility Cardiac myocytes (cardiac muscle cells) experience ↓ contractility ↓ Heart rate ↑ Bleeding Impaired function of the thyroid gland & ↓ thyroid hormone (TH) secretion Pituitary gland secretes ↓ levels of thyroid stimulating hormone (TSH) Hypothyroidism Low or significantly ↓ secretion of triiodothyronine (T3) & thyroxine (T4) from the thyroid gland ↓ T3/T4 levels ↓ production of nitric oxide (vasodilator) & cause systemic vasoconstriction of blood vessels Systemic vaso- constriction ↑ systemic vascular resistance ↑ Systemic vascular resistance à ↑ intrarenal vascular resistance & contributes to ↓ renal perfusion ↓ T3/T4 levels reduce the rate of metabolic reactions in the body including ↓ rates of carbohydrate, fat, & protein metabolism ↓ T3 levels allow fibroblasts (connective tissue cells) to synthesize ↑ glycosaminoglycans (GAGs – structural cell molecules capable of attracting large amounts of water) ↓ Basal metabolic rate (base energy required to sustain bodily functions) ↑ Diastolic blood pressure (diastolic hypertension) ↓ Renal blood flow à ↓ glomerular filtration rate (GFR) ↓ GFR impairs renal clearance of excess GAGs ↑ GAG deposits & water retention in body tissues ↓ Energy to support physiological function Narrowed pulse pressure (↓ difference between systolic & diastolic blood pressure) Compensatory mechanisms to manage blood volume & circulation during ↓ T3/T4 levels are overwhelmed in the presence of an infection or systemic trauma (e.g., heart attack, stroke) ↓ GFR impairs removal of excess free water from the blood volume by the kidneys ↑ GAG deposits & swelling in skin tissue ↑ GAG deposits in the larynx swell & stiffen vocal cords ↓ Skin gland activity & ↓ sebum (oil) & sweat production ↑ Fatigue ↓ Motility of the gastrointestinal (GI) tract causes ↓ movement of digested food & ↓ rate of waste excretion ↓ TH levels & ↓ metabolic rate impair neurologic function (e.g., neurotransmitter signaling & neuron functioning) Thickened skin Hoarse speech Dry skin ↑ Sodium (Na+) & water retention in blood volume ↓ Perspiration (sweating) Constipation Neurologic symptoms (e.g. depression, somnolence) Abnormally heavy menses Excessive water retention dilutes serum Na+ levels in severe hypothyroidism ↓ Caloric expenditure at rest & with activity ↑ Risk of infertility Myxedema coma** (extreme manifestation of hypothyroidism) Hyponatremia (↓ Na+) ↑ Fluid retention in body tissues Weight gain Musculoskeletal symptoms (e.g., muscle cramps, joint pain & ↓ muscle tone) Published June 19, 2013, revised November 23, 2025 on www.thecalgaryguide.com Normal or ↓ TSH levels when T3/T4 levels are low Authors: Sophia Khan, Ayden Hansen, Jessica Revington, Rupali Manek, Jaye Platnich Reviewers: Shahab Marzoughi, Gurreet Bhandal, Raafi Ali, Matthew Harding, Mark Elliott, Hanan Bassyouni*, Breanna McSweeney* * MD at time of publication **See corresponding Calgary Guide slides ↓ T3 levels lead to ↓ lipoprotein lipase (lipid metabolism enzyme) activity ↑ Triglyceride levels in blood ↓ TH levels & ↓ metabolic rate impair cold tolerance & thermogenesis (heat production) mechanisms Cold extremities (e.g. hands, feet) ↓ Cold tolerance ↓ Activation of the T3- mediated low- density lipoprotein (LDL) receptor gene ↓ LDL receptor expression for LDL clearance ↑ LDL cholesterol levels in the blood ↓ T3/T4 levels ↓ coagulation factor synthesis by the liver ↓ T3/T4 levels disrupt the menstrual cycle & cause anovulation (absence of ovulation) Legend: Hyperlipidemia Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Infectious Large Bowel Diarrhea

Infectious large bowel diarrhea: Pathogenesis and clinical findings Bodily fluids, organ transplantation (active in immuno- compromised hosts) Contaminated food, water, poor sanitation Eggs, contaminated Undercooked poultry Undercooked pork Contaminated food, water produce, undercooked poultry Unpasteurized milk Undercooked beef, contaminated vegetables Antibiotic use, healthcare associated infection Cytomegalovirus S. enteritidis, S. Enteroinvasive Enterohemorrhagic typhimurium E. histolytica Y. enterocolitica E. coli (EIEC) Shigella E. coli (EHEC) C. jejuni C. difficile Individual ingests an adequate amount of organism Bacteria employ protective mechanisms to survive gastric acid Organism adheres to colonic wall & colonizes the large bowel Organism releases a toxin that disrupts the colon (enterotoxin) Invading organisms activate local immune surveillance Toxins A & B (from C. diff) disrupt tight junctions between colonocytes Toxin enters bloodstream Release of pro-inflammatory cytokines triggers colonic inflammation Cytokines Inflammation &/or toxins stimulates act on nerve endings hypothalamus in rectal wall to trigger temperature change (pyrogens) Inflammation dysregulates enteric nervous system Inflammation spreads to visceral peritoneum Inflammation & invading bacteria breaks down colonic mucosa Triggers apoptosis of colonocytes Massive neutrophilic infiltration Toxin reaches the chemoreceptor trigger zone in medulla Shiga toxins (from Shigella or EHEC) bind to Gb3 receptors on endothelial cells Pseudomembranous colitis on endoscopy Abnormal peristalsis & spasms Diffuse abdominal pain & cramping Nausea & vomiting Toxin enters cells via endocytosis Fever Colonic epithelium loses Na⁺ resorptive channels Colonic epithelial cells secrete ↑ Cl⁻ into lumen ↑ Sense of urgency & incomplete evacuation (Tenesmus) Inflammation & organisms disrupts blood vessels & mucosa develops ulcers Intestine absorbs ↓ fluid from lumen Intestine secretes ↑ fluid into lumen Shiga toxin activates platelets (mechanism unclear) Toxin inhibits protein synthesis & induces apoptosis Authors: Merry Faye Graff, Noriyah Al Awadhi, Yan Yu Reviewers: Paul Ratti, Jason Baserman, Sergio F. Sharif Kerri Novak*, Sylvain Coderre* *Indicates MD at time of publication **See corresponding Calgary Guide slide Small volume diarrhea Ulcers bleed into colonic lumen Volume depletion Platelet activation & endothelial cell damage promote microthrombi formation within systemic vasculature Dehydration Hypotension Bloody stool (can be nocturnal) Hemolytic uremic syndrome** Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 7, 2012; updated Nov 23, 2025 on www.thecalgaryguide.com

Kawasaki Disease

Kawasaki Disease: Pathogenesis and clinical findings Mutations that ↑ genetic susceptibility (e.g., FCGR2A, CASP3) External trigger such as infection or environmental factor (particulate matter, seasonal airborne antigenic triggers possible) Kawasaki Disease (KD) Acute systemic, inflammatory illness affecting medium-sized arteries (especially coronary arteries), diagnosed clinically with presence of fever & 4/5 of: conjunctivitis, polymorphous rash, cervical lymphadenopathy, mucosal involvement, edema/erythema on hands/feet. KD is the most common cause of acquired heart disease in children in developed countries. Authors: Taylor Krawec, Sunni Ho, Zarrukh Baig, Nissi Wei Reviewers: Merry Faye Graff, Emily J. Doucette, Zaini Sarwar, Mandy Ang, Charissa Chen, Taj Jadavji*, Susanne Benseler*, Danielle Nelson* * MD at time of publication Acute Phase Cytokines disrupt hypothalamic thermoregulation Fever Innate immune cells around medium-sized vessels (especially coronary arteries) are inappropriately activated Neutrophils infiltrate tunica adventitia (outer vessel wall) Coronary arteritis Cytokines enter circulation & mediate systemic inflammation Cervical lymphadenopathy Immune cells infiltrate additional tissue (e.g., lymph nodes, myocardium, pericardium) Myocarditis Pericarditis Local cytokine release Inflammation of tunica media & intima (middle & inner vessel walls) Endothelial activation in small vessels ↑ vasodilation & vessel permeability ↑ Blood flow, plasma leakage & perivascular infiltration of skin & mucosa Strawberry tongue Cracked lips Edema & erythema of hands/feet Bilateral non-exudative conjunctivitis Non-vesicular rash Uveitis Patchy destruction all 3 vessel layers (necrotizing arteritis) but with vessel wall remaining intact Early coronary changes on echocardiogram Subacute Phase / Chronic Vasculitis Vessel walls lose structural integrity Coronary artery aneurysm (rarely other aneurysms) Extensive adaptive immune-mediated destruction of intima, media, elastic lamina & smooth muscle Adaptive immune cells (e.g., eosinophils, plasma cells, lymphocytes) drive ongoing inflammation Damaged vessels disrupt blood flow Thrombus formation Acute myocardial infarction** Systemic inflammation stimulates megakaryocyte proliferation in bone marrow ↑ Platelet production Thrombocytosis Inflammation damages dermis & epidermis Gradual resolution of edema from acute phase & initiation of dermal/epidermal repair Periungal desquamation (peeling of skin around nails) Luminal Myofibroblast Infiltration ↓ Baseline coronary perfusion Coronary flow cannot ↑ to match myocardial O2 demand when needed (demand ischemia) Exertional chest pain or dyspnea Myofibroblasts replace inflammatory infiltrates in vessel walls during chronic healing phase Myofibroblast proliferation thickens intima Affected arteries become narrowed (coronary arteries most common) Exercise intolerance Ischemic myocardium Coronary artery stenosis Arrhythmias is electrically unstable Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 10, 2014; updated Dec 12 2025 on www.thecalgaryguide.com

Inflammatory Versus Degenerative Joint Disease

Legend: Inflammatory vs Degenerative Joint Disease: Pathogenesis & clinical findings Inflammatory Joint Disease The body’s immune system fails to discriminate between self & non-self Autoimmune cells attack body tissues ↑ Synovial (thin lining inside of joints) inflammation ↑ Inflammation dilates blood vessels & activates the endothelium (lining of blood vessels) ↑ Intercellular junctions open à 1hr after waking Legend: Mechanism Sign/Symptom/Lab Finding Systemic immune activation occurs ↑ Inflammatory mediators circulate throughout the body Extra- articular involvement (e.g., skin, eyes, lung, heart, kidneys) ± abnormal inflammatory markers (CRP, ESR) & autoantibodi es (RF, ANA) Pathophysiology Complications Degenerative Joint Disease Abnormal mechanics or repetitive/excessive loading stresses the joints Joint structures degrade over time Movement (using the joint) exacerbates the mechanical forces that are wearing down the joint Pain with movement Pain relieved with rest Fragments of broken articular cartilage triggers a mild synovial (thin lining inside of the joint) inflammation that seeps fluid into the synovial membrane during inactivity Joints stiffen with rest Moving the joint physically pushes inflammatory fluid back into lymphatic vessels (body's clean- up system) within minutes Joint stiffness resolves within minutes of movement Published on www.thecalgaryguide.com Authors: Yan Yu Mackenzie Trpcic Reviewers: Jennifer Au Sean Spence Martin Atkinson* Catherine R Jarvis * MD at time of publication The weight- bearing joints (i.e., knee, hip, & lumbar/cervical facet joints) sustain the highest mechanical load & degeneration Distinguishing between Inflammatory and Degenerative joint disease Inflammatory Joint Disease Auto-immune attack of body tissues, due to failure of the body’s immune system to discriminate between self and non-self. Degenerative Joint Disease Repetitive, excess, or abnormal mechanical forces on joints over time, leading to physical breakdown of the joint. Authors: Yan Yu Reviewers: Jennifer Au Sean Spence Martin Atkinson* * MD at time of publication Within joints, severe synovial inflammation dilates local blood vessels, and causes the vessel endothelium to be more leaky. Accumulation of abundant inflammatory synovial fluid at rest or overnight Swelling stimulates joint nociceptors Pain with rest Moving the joint physically pushes fluid back into lymphatics, relieving the painful swelling. Pain relieved with motion Legend: Overnight fluid accumulation in the synovial membrane Morning stiffness Lots of fluid, takes more time (hours) to be reabsorbed by lymphatics Stiffness resolves after >1hr Blood carries heat and looks red Warm, Red, Swollen Joints Pathophysiology Mechanism Sign/Symptom/Lab Finding Inflammation is oftentimes systemic, not localized exclusively within the joint (i.e. in Rheumatoid arthritis, Lupus, etc) Extra-articular manifestations; positive inflammatory markers (CRP, ESR, RF, ANA) Motion (using the joint) exacerbates the mechanical forces that are wearing down the joint Fragments of broken articular cartilage triggers a mild synovial inflammation that seeps fluid into the synovial membrane during inactivity Pain with motion (relieved by rest) Joint stiffness after inactivity Moving the joint physically pushes inflammatory fluid back into lymphatics within minutes. Note: one big difference btw the two is the degree of joint inflammation (synovitis) present in the joint capsule Stiffness is short-lived, quickly relieved by movement Published November1,2012 on www.thecalgaryguide.com Larger, weight- bearing joints tend to bear the brunt of the mechanical forces Most commonly affects the knee, hip, and L/C-spine facet joints Complications" title="Legend: Inflammatory vs Degenerative Joint Disease: Pathogenesis & clinical findings Inflammatory Joint Disease The body’s immune system fails to discriminate between self & non-self Autoimmune cells attack body tissues ↑ Synovial (thin lining inside of joints) inflammation ↑ Inflammation dilates blood vessels & activates the endothelium (lining of blood vessels) ↑ Intercellular junctions open à "leaky" blood vessels Synovial fluid accumulates & causes joint edema (swelling) ↑ Blood flow carries heat to affected joint tissues Edema (swelling) Warmth Erythema (redness) Fluid builds in the synovial membrane overnight Morning joint stiffness Swelling activates joint nociceptors (damage alarms) Pain worse with rest Systemic immune activation occurs ↑ Inflammatory mediators circulate throughout the body Extra- articular (body tissues outside of joints) inflammatory damage ± ↑ Inflammatory markers (CRP, ESR) ± ↑ Auto- antibodies (RF, ANA) Lymphatic vessels (the body’s cleaning system) need ↑ time to reabsorb ↑ fluid that accumulated overnight Joint stiffness resolves ~1 hour after waking Movement (using the joint) pushes fluid into lymphatic vessels (the body’s cleaning system) Pain relieved with movement Degenerative Joint Disease Abnormal mechanics (e.g., poor posture, weak stabilizing muscles) Repetitive or excess stress on joints Weight bearing joints (knee, hip & lumbar/cervical facet joints) sustain the highest mechanical load & degenerate over time Fragments of articular (joint) cartilage trigger a synovial (thin lining inside of joints) inflammation Movement (using the joint) exacerbates the mechanical forces wearing down the joint Inflammation causes fluid to seep into the synovial membrane during inactivity Pain with movement Pain relieved with rest Joints stiffen with rest Movement (using the joint) pushes fluid back into lymphatic vessels (the body’s cleaning system) Joint stiffness resolves within minutes of movement Authors: Yan Yu Mackenzie Trpcic Reviewers: Jennifer Au Sean Spence Catherine R Jarvis Martin Atkinson* Glen Hazlewood* * MD at time of publication Published Nov 1, 2012; updated Feb 1, 2026 on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Final slide is the 1st slide Legend: Inflammatory vs Degenerative Joint Disease: Pathogenesis & clinical findings Inflammatory Joint Disease Degenerative Joint Disease The body’s immune system fails to discriminate between self & non-self Autoimmune cells attack body tissues Abnormal mechanics (e.g., poor posture, weak stabilizing muscles) Repetitive or excess stress on joints ↑ Synovial (thin lining inside of joints) inflammation dilates blood vessels Systemic immune activation occurs ↑ Endothelium (lining of blood vessels) activation opens intercellular junctions (“leaky” blood vessels”) ↑ Inflammatory mediators circulate throughout the body Weight bearing joints (knee, hip & lumbar/cervical facet joints) sustain the highest mechanical load & degenerate over time Synovial fluid accumulates & causes joint edema (swelling) Edema (swelling) ↑ Blood flow carries heat to affected joint tissues Extra- articular (body tissues outside of ± ↑ Inflammatory markers (CRP, ESR) ± ↑ Auto- antibodies (RF, ANA) Fragments of articular (joint) cartilage trigger a synovial (thin lining inside of joints) inflammation Movement (using the joint) exacerbates the mechanical forces wearing down the joint joints) inflammatory Inflammation causes Warmth Pain relieved Erythema damage fluid to seep into the Pain with (redness) synovial membrane movement with rest during inactivity Fluid builds in the synovial membrane overnight Morning joint stiffness Lymphatic vessels (cleaners) need ↑ time to reabsorb ↑ fluid that accumulated overnight Joints stiffen with rest Joint stiffness resolves ~1 hour after waking Movement (using the joint) pushes fluid back into lymphatic vessels (cleaners) Swelling activates joint nociceptors (damage alarms) Pain worse with rest Movement (using the joint) pushes fluid into lymphatic vessels (cleaners) Pain relieved with movement Joint stiffness resolves within minutes of movement Authors: Yan Yu Mackenzie Trpcic Reviewers: Jennifer Au Sean Spence Martin Atkinson* Catherine R Jarvis * MD at time of publication Published on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Inflammatory vs Degenerative Joint Disease: Pathogenesis & clinical findings Inflammatory Joint Disease Degenerative Joint Disease The body’s immune system fails to discriminate between self & non-self Auto-immune cells attack body tissues Abnormal mechanics (e.g., poor posture, weak stabilizing muscles) Repetitive or excess stress on joints ↑ Synovial (thin lining inside of joints) inflammation dilates blood vessels Systemic immune activation occurs ↑ Endothelium (lining of blood vessels) activation opens intercellular junctions (“leaky” blood vessels”) ↑ Inflammatory mediators circulate throughout the body Weight bearing joints (knee, hip & lumbar/cervical facet joints) sustain the highest mechanical load & degenerate over time Synovial fluid accumulates & leads to joint edema (swelling) ↑ Blood flow carries heat to affected joint tissues Swelling activates joint nociceptors (damage alarms) Fluid builds in the synovial membrane overnight Edema (swelling) Warmth Erythema (redness) Extra-articular (body tissues outside of joints) inflammatory damage ± ↑ Inflammatory markers (CRP, ESR) & auto- antibodies (RF, ANA) Movement (using the joint) exacerbates the mechanical forces wearing down the joint Pain with movement Pain relieved with rest Pain worse with rest Morning joint stiffness Movement (using the joint) pushes fluid into lymphatic vessels (cleaners) Lymphatic vessels (cleaners) need ↑ time to reabsorb ↑ fluid overnight Pain relieved with movement Joint stiffness resolves ~1 hour after waking Authors: Yan Yu Mackenzie Trpcic Reviewers: Jennifer Au Sean Spence Martin Atkinson* Catherine R Jarvis * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Fragments of articular (joint) cartilage trigger a synovial (thin lining inside of joints) inflammation Inflammation causes fluid to seep into the synovial membrane during inactivity Joints stiffen with rest Movement (using the joint) pushes inflammatory fluid back into lymphatic vessels (cleaners) Joint stiffness resolves within minutes of movement Published on www.thecalgaryguide.com Inflammatory vs Degenerative Joint Disease: Pathogenesis & clinical findings Inflammatory Joint Disease The body’s immune system fails to discriminate between self and non-self Auto-immune cells attack body tissues ↑ Synovial (thin lining inside of joints) inflammation dilates blood vessels ↑ Endothelium (lining inside of blood vessels) permeability Synovial fluid accumulates & leads to joint edema (swelling) Systemic immune activation occurs ↑ Inflammatory mediators circulate throughout the body Extra-articular involvement (body tissues outside of joints) Elevated inflammatory markers (CRP, ESR) & auto- antibodies (RF, ANA) Degenerative Joint Disease Abnormal mechanics (e.g., poor posture, weak stabilizing muscles) Repetitive/excess stress on joints Weight bearing joints (knee, hip & lumbar/cervical facet joints) sustain the highest mechanical load & degenerate over time Movement (using the joint) exacerbates the mechanical forces wearing down the joint Pain with movement Pain relieved with rest Authors: Yan Yu Mackenzie Trpcic Reviewers: Jennifer Au Sean Spence Martin Atkinson* Catherine R Jarvis * MD at time of publication Swelling activates pain-sensitive joint nociceptors (damage alarms) Pain worse with rest Joint movement pushes fluid into lymphatic vessels (body's clean-up system) Pain relieved with movement Legend: ↑ Blood flow carries heat to affected joint tissues Edema (swelling) Warmth Erythema (redness) Fluid gradually builds in the synovial membrane overnight Morning joint stiffness Lymphatic vessels (body's clean-up system) need ↑ time to reabsorb ↑ fluid that accumulated overnight Joint stiffness resolves ~1 hour after waking Fragments of articular (joint) cartilage trigger a synovial (thin lining inside of joints) inflammation Inflammation causes fluid to seep into the synovial membrane during inactivity Joints stiffen with rest Moving the joint physically pushes inflammatory fluid back into lymphatic vessels (body's clean-up system) Joint stiffness resolves within minutes of movement Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published on www.thecalgaryguide.com JOINT DISEASE: Inflammatory vs. Degenerative Inflammatory Joint Disease The body’s immune system fails to discriminate between self and non-self Auto-immune cells attack body tissues ↑ Synovial (thin lining inside of the joint) inflammation dilates blood vessels ↑ Endothelium (inner lining of blood vessels) permeability Synovial fluid accumulates & leads to joint edema (swelling) ↑ Blood flow carries heat to affected joint tissues Swelling activates pain-sensitive joint nociceptors (damage alarms) Fluid accumulates progressively in the synovial membrane overnight Edema (swelling) Warmth Inflammatory pain worse with rest Morning joint stiffness Erythema (redness) Joint movement physically pushes fluid back into lymphatic vessels (body's clean-up system) Lymphatic vessels (body's clean-up system) need ↑ time to reabsorb the ↑ fluid that accumulated overnight Inflammatory pain relieved with activity Joint stiffness resolves > 1hr after waking Legend: Mechanism Sign/Symptom/Lab Finding Systemic immune activation occurs ↑ Inflammatory mediators circulate throughout the body Extra- articular involvement (e.g., skin, eyes, lung, heart, kidneys) ± abnormal inflammatory markers (CRP, ESR) & autoantibodi es (RF, ANA) Pathophysiology Complications Degenerative Joint Disease Abnormal mechanics or repetitive/excessive loading stresses the joints Joint structures degrade over time Movement (using the joint) exacerbates the mechanical forces that are wearing down the joint Pain with movement Pain relieved with rest Fragments of broken articular cartilage triggers a mild synovial (thin lining inside of the joint) inflammation that seeps fluid into the synovial membrane during inactivity Joints stiffen with rest Moving the joint physically pushes inflammatory fluid back into lymphatic vessels (body's clean- up system) within minutes Joint stiffness resolves within minutes of movement Published on www.thecalgaryguide.com Authors: Yan Yu Mackenzie Trpcic Reviewers: Jennifer Au Sean Spence Martin Atkinson* Catherine R Jarvis * MD at time of publication The weight- bearing joints (i.e., knee, hip, & lumbar/cervical facet joints) sustain the highest mechanical load & degeneration Distinguishing between Inflammatory and Degenerative joint disease Inflammatory Joint Disease Auto-immune attack of body tissues, due to failure of the body’s immune system to discriminate between self and non-self. Degenerative Joint Disease Repetitive, excess, or abnormal mechanical forces on joints over time, leading to physical breakdown of the joint. Authors: Yan Yu Reviewers: Jennifer Au Sean Spence Martin Atkinson* * MD at time of publication Within joints, severe synovial inflammation dilates local blood vessels, and causes the vessel endothelium to be more leaky. Accumulation of abundant inflammatory synovial fluid at rest or overnight Swelling stimulates joint nociceptors Pain with rest Moving the joint physically pushes fluid back into lymphatics, relieving the painful swelling. Pain relieved with motion Legend: Overnight fluid accumulation in the synovial membrane Morning stiffness Lots of fluid, takes more time (hours) to be reabsorbed by lymphatics Stiffness resolves after >1hr Blood carries heat and looks red Warm, Red, Swollen Joints Pathophysiology Mechanism Sign/Symptom/Lab Finding Inflammation is oftentimes systemic, not localized exclusively within the joint (i.e. in Rheumatoid arthritis, Lupus, etc) Extra-articular manifestations; positive inflammatory markers (CRP, ESR, RF, ANA) Motion (using the joint) exacerbates the mechanical forces that are wearing down the joint Fragments of broken articular cartilage triggers a mild synovial inflammation that seeps fluid into the synovial membrane during inactivity Pain with motion (relieved by rest) Joint stiffness after inactivity Moving the joint physically pushes inflammatory fluid back into lymphatics within minutes. Note: one big difference btw the two is the degree of joint inflammation (synovitis) present in the joint capsule Stiffness is short-lived, quickly relieved by movement Published November1,2012 on www.thecalgaryguide.com Larger, weight- bearing joints tend to bear the brunt of the mechanical forces Most commonly affects the knee, hip, and L/C-spine facet joints Complications" />

Necrosis versus Apoptosis

Necrosis vs Apoptosis: Pathogenesis and clinical findings Toxic chemicals (poisons, drug toxicities) Hypoxia (↓ Oxygen delivered to tissues) Physical agents (extreme temperatures, trauma, radiation) Bacterial, viral, or fungal infections &/or microbe toxins Necrosis Uncontrolled & pathologic cell death Harmful stimuli trigger ↓ ATP (cellular energy) ↓ ATP leads to ion pump failure & ↑ cell permeability (“leakiness”) ↑ Cellular ion influx causes cell to swell & lyse (rupture its plasma membrane) Intracellular contents spill into the extracellular space Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Pro-inflammatory cytokine interleukin-1β is secreted & activates the immune system Excessive cytokine release provokes a large inflammatory response Inflammation damages surrounding healthy tissues & organs Ischemia (↓ Blood flow) to organs except brain ↓ Oxygen denatures enzymes à dead cell skeletons cannot breakdown Cells remain “coagulated” (firm) for days Coagulative necrosis ↓ Blood flow to limb(s) +/- bacterial invasion Gangrenous necrosis ↑ Pain or ↓ feeling in affected limb(s) Skin color changes (red, purple, black) Damaged adipocytes (fat cells) release triglyceride (fat) contents that group into oil cysts Scars form & calcify (harden) Fat necrosis Damaged endothelium (blood vessel wall) becomes leaky Fibrin (blood protein) deposits in endothelium with immune complexes Fibrinoid necrosis Brain ischemia &/or infection kills cells Digestive enzymes transform dead tissue into creamy liquid pus Liquefactive necrosis Coagulative + liquefactive necrosis mechanisms à granular debris Caseous necrosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ----------------------------------------------------------------------------------------------------- Authors: Tyra Fernandes Catherine R Jarvis Reviewers: Mitchell Chorney Sarah Smith* * MD at time of publication Apoptosis Programmed cell death via an energy-dependent process Extrinsic pathway: cellular stress or damage signals in the extracellular environment trigger apoptosis Intrinsic pathway: internal cellular stressors (damage from chemotherapy, UV radiation, drugs) trigger apoptosis Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) & FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Pro-apoptotic factors recognize cellular stressors Cytochrome C releases from the intermembrane space of the mitochondria to the cytoplasm Ligand binding activates initiator caspases (protease (protein breakdown)-like enzymes) 2, 8, 9, 10 Cytochrome C activates Caspase-9 Initiator caspases activate effector caspases 3, 6, 7 Caspase-9 activates effector caspases 3 & 7 Effector caspases begin execution pathway Caspases degrade the cell’s nuclear envelope & DNA à DNA repair is inhibited & cell shrinks Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published Feb 8, 2026 on www.thecalgaryguide.com Final Slide is 1st Necrosis vs Apoptosis: Pathogenesis and clinical findings Toxic chemicals (poisons, drug toxicities) Hypoxia (↓ Oxygen delivered to tissues) Physical agents (extreme temperatures, trauma, radiation) Toxin release from bacteria, viruses, or fungi Necrosis Uncontrolled & pathologic cell death Harmful stimuli trigger ↓ ATP (cellular energy) ↓ ATP leads to ion pump failure & ↑ cell permeability ↑ Cellular ion influx causes cell to swell & lyse (rupture its plasma membrane) Intracellular contents spill into the extracellular space Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Inflammation damages surrounding healthy tissues & organs Ischemia (↓ Blood flow) to organs except brain ↓ Oxygen denatures enzymes à cell skeleton cannot be broken down Cell is preserved in “coagulated” state for days Coagulative necrosis ↓ Blood flow to limbs +/- bacterial invasion Gangrenous necrosis ↑ Pain or ↓ feeling in limb Skin color changes (red, purple, black) Damaged adipocytes (fat cells) release triglycerides (fat) contents that group into oil cysts Scars form & calcify (harden) Fat necrosis Damaged endothelium (blood vessel wall) becomes leaky Fibrin (blood protein) deposits in endothelium with immune complexes Fibrinoid necrosis Brain ischemia &/or infection kills cells Digestive enzymes transform dead tissue into creamy liquid pus Liquefactive necrosis Coagulative & liquefactive necrosis mixture à granular debris Caseous necrosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding ----------------------------------------------------------------------------------------------------- Complications Authors: Tyra Fernandes Catherine R Jarvis Reviewers: Mitchell Chorney Sarah Smith* * MD at time of publication Apoptosis Programmed cell death via an energy-dependent process Extrinsic pathway: cellular stress or damage signals in the extracellular environment trigger apoptosis Intrinsic pathway: internal cellular stressors (chemotherapy, UV radiation, drugs, misfolded proteins) trigger apoptosis Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) & FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Pro-apoptotic factors recognize cellular stressors Cytochrome C releases from the intermembrane space of the mitochondria to the cytoplasm Ligand binding activates initiator caspases (protease (protein breakdown)-like enzymes) 2, 8, 9, 10 Cytochrome C activates Caspase-9 Initiator caspases activate effector caspases 3, 6, 7 Caspase-9 activates effector caspases 3 & 7 Effector caspases begin execution pathway Caspases degrade the cell’s nuclear envelope & DNA à DNA repair is inhibited & cell shrinks Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Necrosis vs Apoptosis Toxic chemicals (poisons, drug toxicities) Hypoxia (↓ Oxygen delivered to tissues) Physical agents (extreme temperatures, trauma, radiation) Biological agents (bacteria, viruses, fungi) Necrosis Non-physiologic & uncontrolled cell death Noxious (harmful) stimuli trigger increased cell permeability and ion pump failure Cell swells & ruptures its plasma membrane à cell lysis (breakdown) Intracellular contents spill into the extracellular space Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Inflammation damages surrounding healthy tissues & organs Acute tubular necrosis (damaged kidney tubule cells) Gangrene (body tissue death) Myocardial infarction (heart attack) Steatohepatitis (progressive liver disease) ↓ Blood flow to a Myocardium (heart portion of the body muscle) is deprived Necrotic renal (usually limbs) of oxygen & (kidney) tubular becomes damaged epithelial cells deteriorate & slough off ↑ Extracellular matrix proteins (especially collagen) are produced and deposit in liver Granular casts on urine microscopy ↑ Pain or ↓ Feeling Skin color change (red, purple, black) ↑ Blood troponin levels ↓ Heart function Liver fibrosis (scarring) Legend: Authors: Tyra Fernandes Catherine R Jarvis Reviewers: ----------------------------------------------------------------------------------------------------- Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Mitchell Chorney Name Name* * MD at time of publication Apoptosis Programmed cell death via an energy-dependent process Extrinsic Pathway: Apoptotic signals from other cells cause initiation Intrinsic Pathway: Internal cellular stressors (chemotherapy, UV radiation, drugs, misfolded proteins) cause initiation Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) & FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Pro-apoptotic factors recognize cellular stressors Cytochrome P releases from the intermembrane space of the Ligand binding activates initiator mitochondria to the cytoplasm caspases (protease (protein breakdown)-like enzymes) 2, 8, 9, 10 Cytochrome P activates Caspase-9 Initiator caspases activate effector caspases 3, 6, 7 Caspase-9 activates caspases 3 & 7 Execution Pathway Caspases degrade the cell’s nuclear envelope & DNA à DNA repair is inhibited & cell shrinks Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Necrosis vs Apoptosis Hypoxia Chemical agents Physical agents Biological agents Necrosis Non-physiologic & uncontrolled cell death Oncolysis (ion pump failure and increased cell permeability cause cell swelling) occurs due to noxious stimuli Plasma membrane ruptures and cell is lysed (broken down) Intracellular contents spill into the extracellular space Authors: Tyra Fernandes Reviewers: Mitchell Chorney Catherine R Jarvis Name Name* * MD at time of publication Renal tubule is damaged due to reduced oxygen supply and toxicity Granular casts on urine microscopy Acute tubular necrosis (kidney disorder of the tubule cells Extracellular matrix proteins accumulate in liver causing collagen deposition Liver fibrosis Steatohepatitis (progressive liver disease) Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Myocardium (heart muscle) is deprived of oxygen ↑ Blood troponin levels Myocardial infarction ----------------------------------------------------------------------------------------------------- Apoptosis Programmed cell death via an energy-dependent process Extrinsic Pathway: Apoptotic signals from other cells cause initiation Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) and FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Ligand binding activates initiator caspases (protease-like enzymes) 2, 8, 9, 10 Initiator caspases activate effector caspases 3, 6, 7 Intrinsic Pathway: Internal cellular stressors (chemotherapy, UV radiation, drugs, & misfolded proteins) cause initiation Pro-apoptotic factors recognize cellular stressors Cytochrome P releases from the intermembrane space of the mitochondria to the cytoplasm Cytochrome P activates Caspase-9 Caspase-9 activates caspases 3 & 7 Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Legend: Inflammatory damage to the surrounding healthy tissues Microscopic Effects: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Execution Pathway Caspases degrade the cell’s nuclear envelope. DNA fragments inhibit DNA repair, which shrinks the cell Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Necrosis vs Apoptosis Authors: Tyra Fernandes Reviewers: Mitchell Chorney Catherine R Jarvis Hypoxia, physical agents, chemical agents, biologic agents Necrosis (Non-physiologic & uncontrolled cell death) Oncolysis (cell swelling due to the failure of ion pumps and increased cell permeability) occurs due to noxious stimuli Plasma membranes rupture leading to cell lysis Intracellular contents spill into the extracellular space Inflammasomes (cytoplasmic multiprotein complexes) are activated Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Legend: Microscopic Effects: Steatohepatitis Collagen deposition due to the accumulation of extracellular matrix proteins Liver fibrosis Myocardial Infarction Ischemic or toxic injury to the renal tubule Granular casts on urine microscopy Acute tubular necrosis Oxygen supply deprivation to the myocardium Elevated blood troponin levels ----------------------------------------------------------------------------------------------------- Extrinsic Pathway: Apoptotic Signals from other cells cause initiation Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) and FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Ligand binding activates initiator caspases (protease-like enzymes) 2, 8, 9, 10 Initiator caspases activate effector caspases 3, 6, 7 Apoptosis (Programmed cell death via an energy- dependent process) Name Name* * MD at time of publication Intrinsic Pathway: Internal cellular stressors chemotherapy, UV radiation, drugs, & misfolded proteins) cause initiation Pro-apoptotic factors recognize cellular stressors Cytochrome P releases from the intermembrane space of the mitochondria to the cytoplasm Cytochrome P activates Caspase-9 Caspase-9 activates caspases 3 and 7 Execution Pathway Cellular shrinkage forms apoptotic bodies Inflammatory damage to surrounding healthy tissues à potential organ failure Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications The nuclear envelope degrades and DNA fragments which inhibits DNA repair which shrinks the cell Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Authors: Necrosis vs Apoptosis Tyra Fernandes Reviewers: Mitchell Chorney Necrosis Apoptosis Catherine R Jarvis Hypoxia: ischemia, respiratory insufficiency Physical agents: trauma, radiation, Non-physiologic & temperature, electrical shock uncontrolled cell death Biological agents: bacteria, viruses, fungi Chemical agents: poisons, drugs, Cell swelling (oncosis) due to occupational exposures the failure of ion pumps and increased cell permeability Collagen deposition leading to liver fibrosis Cell lysis due to the rupture of the plasma membrane Steatohepatitis Microscopic Spillage of intracellular contents Effects: into the extracellular space Acute tubular Myocardial Activation of cytoplasmic necrosis Infarction multiprotein complexes, known as inflammasomes Ischemic or toxic Oxygen supply injury to the renal deprivation to the tubule myocardium Secretion of pro-inflammatory cytokine interleukin-1β, which ----------------------------------------------------------------------------------------------------- Name Name* * MD at time of publication Programmed cell death via an energy-dependent process Extrinsic pathway Intrinsic pathway The cell receives apoptotic signals Initiated by internal cellular from other cells stressors such as chemotherapy drugs, UV radiation, and misfolded Apoptosis is activated via ligands proteins binding to apoptotic receptors on the cell surface Pro-apoptotic factors recognize cellular stressors Ligand binding activates initiator caspases (2, 8, 9, 10), which are Cytochrome P releases from the protease-like enzymes intermembrane space of the mitochondria to the cytoplasm Examples of ligands include: TNF-α (produced by macrophages) and Caspase-9 is activated FasL (produced by T cells) Activation of downstream effector Effector caspases (3, 6, 7) are caspases 3 and 7 activated activates the immune system Excessive cytokine release provokes a large inflammatory response Legend: Granular casts on urine microscopy Elevated blood troponin levels Damage to surrounding healthy tissues may lead to organ failure Prevention of inflammation Execution pathway The nuclear envelope degrades and DNA fragments which inhibits DNA repair Cellular shrinkage forms apoptotic bodies Phagocy engulfment of apoptotic bodies Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Necrosis versus apoptosis Necrosis Non-physiologic & uncontrolled cell death due to noxious stimuli Cell swelling (oncosis) à cell lysisà spillage of intracellular contents à tissue damage Inflammatory response, leading to inflammasome activation and the secretion of pro-inflammatory cytokine interleukin-1β Macroscopic Effects: Hypoxia: ischemia, respiratory insufficency Physical agents: trauma, radiation, temperature, electrical shock Biological agents: bacteria, viruses, fungi Chemical agents: poisons, drugs, occupational exposures Acute tubular necrosis due to chemical agents Myocardial infarction due to hypoxia Microscopic Effects: Stroke due to hypoxia in the brain Gangrene due to hypoxia of the limbs Steatohepatitis due to chemical agents ----------------------------------------------------------------------------------------------------- Apoptosis Programmed cell death via an energy-dependent process Execution phase: pro-& anti- apoptotic proteins mediate cell breakdown by caspases Caspase activity blocks DNA repair à leading to fragmented DNA and cell shrinkage Apoptosis is inhibited in cancer the overexpression of anti-apoptotic proteins Authors: Tyra Fernandes Reviewers: Mitchell Chorney Name Name* * MD at time of publication Extrinsic pathway: immune cell activation activates executioner caspases; ligands such as TNF-α & FasL bind to receptors on the cell membrane Intrinsic pathway: internal cellular factors cause pro-apoptotic factors to increase mitochondrial membrane permeability. Cytochrome c is released from the inner mitochondrial membrane, which ultimately activates caspases Cellular fragments are engulfed by immune cells which prevents an inflammatory response Organism death via necrosis Menstruation Embryogenesis Endometrial shedding of the inner lining of the uterus is an apoptotic mechanism The tissue between the fingers and toes degrades via apoptosis in utero à separation of the digits Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Abbreviations: • IL-1β– interleukin-1β • TNF-α– tumour necrosis factor - alpha • FasL– CD95 ligand; mediates apoptosis Published MONTH, DAY, YEAR on www.thecalgaryguide.com Complications References • https://next.amboss.com/us/article/VP0GdT?q=apoptosis#Y0d79977cce8fc2c548ac720f8060d667 • https://www.ncbi.nlm.nih.gov/books/NBK557627/ • https://www.ncbi.nlm.nih.gov/books/NBK499821/ • https://pmc.ncbi.nlm.nih.gov/articles/PMC5855670/ • https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/oncosis • https://www.nature.com/articles/s41421-020-0167-x • https://pmc.ncbi.nlm.nih.gov/articles/PMC3714593/ • https://www.ncbi.nlm.nih.gov/books/NBK537076/ Hypoxia Physical agents Biological agents Chemical agents

Coxsackie, Echo, and Entero-viruses; including Hand, Foot, & Mouth Disease

Coxsackie, Echo, and Entero-viruses; including Hand, Foot, & Mouth Disease Infected host sheds virus from gastrointestinal tract, upper respiratory tract, vesicles, &/or oral secretions Innate immune cells identify and mount immune response to virus ↑ Cytokines & chemokines from immune cells triggers inflammatory response Local tissue damage from cellular inflammatory response creates edema and activates pain receptors in the throat Contact and droplet transmission of coxsackievirus A16 (CV-A16 or enterovirus 71 (EV-A71) Virus replicates in intestinal & pharyngeal lymphoid tissue & spreads to regional lymph nodes Virus spreads to various target tissues via blood (viremia) Systemic inflammatory cytokines trigger hypothalamus to ↑ temperature Fever Sore, swollen throat Viral replication creates vesicles in oral mucosa, which rapidly rupture to create ulcers Enanthem in mucous membranes of mouth Sores & inflammation cause painful swallowing, preventing fluid intake Clusters of macules & papules (immunopathologic response) and vesicles (pathogenic response) develops on palms of hands, & soles of feet Dehydration EV-A71 targets pulmonary epithelial cells and thus proliferate in lung tissue Brainstem encephalitis or systemic inflammation possibly ↑ vascular permeability in lungs (exact mechanism unknown) Pulmonary hemorrhage Pulmonary edema Legend: Virus replicates in squamous epithelial cells via SCARB2 proteins, which are abundant in the hands, feet & mouth Virus causes keratinocytes to swell and degenerate and burst, resulting in edema of the papillary dermis EV-A71 targets specific neuronal & neuromuscular proteins, thus proliferating in central nervous system and muscle Virus causes infection & swelling of the meninges & cerebrospinal fluid Viral meningitis EV-A71 attaches to white blood cells, passes through the blood brain barrier, & triggers brain inflammation Brainstem encephalitis Possible injury to nail matrix from damage to keratinocytes in nail bed (exact mechanism unknown) Onychomadesis (nail shedding) Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Authors: Alua Kulenova Reviewers: Emily J. Doucette Brandon Christensen* *MD at time of publication **See corresponding Calgary Guide slide Published Feb 17, 2026 on www.thecalgaryguide.com hand foot mouth hfm disease

Cryoglobulinemia

Cryoglobulinemia: Pathogenesis and clinical findings Inflamed vasculature Seizure is predisposed to Hemorrhagic stroke (blood Lymphoproliferative Hematologic Hepatitis C Autoimmune (self- Deposits in rupture & ↓ seizure vessel leaks into brain) (↑ Lymphocyte (blood) cancers infection (HCV) attacking) conditions cerebral Cerebral threshold production) conditions (brain) vasculitis Ischemic stroke (clot blocks Inflamed vasculature arteries ↓ cerebral blood flow cerebral blood flow) Acute ↑ B cell activity ↑ Chronic B cell activation ↑ Deposits in Retinal Retinal artery hemorrhage (severe bleeding) immunoglobulin (Ig) production immunoglobulin (Ig) production retinal arteries vasculitis Retinal artery infarct (↓ oxygenation à tissue death) of eyes Tingling Type II: Type III: Deposits damage & narrow walls of ↓ Blood flow monoclonal (recognize 1 polyclonal tiny blood vessels supplying to nerve cells Numbness Type I: site on antigen) IgM, IgG or (recognize >1 nutrients to peripheral nerves Weakness monoclonal (recognize 1 IgA & polyclonal (recognize site on antigen) site on antigen) IgM or IgG >1 site on antigen) Igs IgG & IgM Deposits in Alveolar alveolar (lung air capillaries are sacs) capillaries destroyed Exposure to temperatures <37°C Immune complexes deposit & form cryoglobulin (abnormal protein) in small/medium-sized vessels Cryoglobulins activate complement (factors that enhance innate (first-line) immune system responses) Deposits in cardiac (heart) tissue Deposits obstruct mesenteric (abdominal) vasculature Myocardial (heart muscle) inflammation, necrosis & fibrosis (scarring) Mesenteric vasculitis Alveolar Dyspnea (short of breath) hemorrhage (severe bleeding) Hemoptysis (coughing blood) Hypoxia (↓ Tissue oxygenation) Myocarditis (inflamed myocardium)** Inflamed vasculature Gastrointestinal à ↑ rupture risk bleed Mesenteric ischemia (↓ ↓ Mesenteric blood flow oxygen to intestines) à scars & narrows intestines Complement factors are consumed (activated & used) Immune complexes (primarily type I) occlude vessels Immune complexes (primarily types II & III) deposit in vessels à endothelial (vessel wall) damage & vasculitis (inflammation) Abdominal pain Abdominal cramps Bowel obstruction Deposits damage glomeruli (kidney capillary clusters) à triggers inflammation ↑ Permeability (“leakiness”) in damaged capillaries Hematuria (blood in urine) Proteinuria (protein in urine) ↓ Complement factors C3 & C4 Blood in obstructed vessel areas becomes hyper-viscous (thick) Hyperviscosity syndrome Inflammation ↑ proliferation of glomerular basement Blood stasis & vascular congestion ↓ Oxygen delivered to skin Local hypoxia (↓ oxygen delivery) Visual disturbances Confusion Headache Membranoproliferative glomerulonephritis (immune-mediated kidney inflammation) Joint swelling Joint stiffness ↑ Hydrostatic pressure ruptures capillaries Livedo reticularis (reddish-blue patchy skin discolouration) Reactive vasoconstriction (narrowed vessels) Deposits in synovial (joint connective tissue) membrane Deposits damage post- capillary venules in dermis (skin) Red blood cells leak into surrounding tissue Mucosal (moist lining of Raynaud phenomena (extremities exposed tissues) bleeding become white & numb Vasoconstriction obstructs blood vessels Ischemia (restricted blood supply to tissues) Synovial edema (swelling) & thickening Non-blanchable (non-color- fading) purpura (palpable purple skin spots) Necrosis (cell & tissue death)** Authors: Julia Fox, Catherine R Jarvis Reviewers: Navdeep Goraya, Glen Hazlewood* * MD at time of publication **See corresponding Calgary Guide slide(s) Legend: Pathophysiology Mechanism Complications Published Mar 1, 2026 on www.thecalgaryguide.com ↓ Blood flow Sign/Symptom/Lab Finding